CN109963588A - 抗ctla4抗体 - Google Patents
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- CN109963588A CN109963588A CN201780052212.6A CN201780052212A CN109963588A CN 109963588 A CN109963588 A CN 109963588A CN 201780052212 A CN201780052212 A CN 201780052212A CN 109963588 A CN109963588 A CN 109963588A
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- C12N2015/8518—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles
Abstract
本发明属于肿瘤疗法和分子免疫学的领域。本发明涉及抗CTLA4抗体、药物组合物及其用途。本发明的抗CTLA4抗体可以特异性结合CTLA4,并且可以非常有效地阻断CLTA4与B7的结合。
Description
序列表
本申请含有已经以ASCII形式电子提交且在此以其整体通过引用并入的序列表。所述ASCI拷贝,在2017年8月15日生成,名为24359-US-PCT_SL.txt,且大小为34,800字节。
发明领域
本发明属于肿瘤疗法和分子免疫学的领域。本发明涉及抗CTLA4抗体、药物组合物及其用途。
发明背景
细胞毒性T淋巴细胞相关抗原4(缩写为CTLA4)与CD28分子在基因结构、染色体位置、序列同源性和基因表达方面具有非常密切的关系。它们两者均为共刺激分子B7的受体,主要在活化的T细胞表面上表达。与B7结合之后,CTLA4可以抑制小鼠和人T细胞的活化,在T细胞的活化中起负调节作用。
CTLA4 mAb或CTLA4配体可以阻止CTLA4与其天然配体结合,由此阻断通过CTLA4的T细胞负调节信号的转导,并增强T细胞对各种抗原的反应性。在这方面,来自体内和体外研究的结果是实质上一致的。目前,有一些CTLA4 mAb正在临床试验中测试用于治疗前列腺癌、膀胱癌、结肠直肠癌、胃肠道癌、肝癌、恶性黑色素瘤等。(CTLA-4 blockade in tumormodels: an overview of preclinical and translational research. Grosso JF.,Jure-Kunkel MN., Cancer Immun. 2013; 13:5. 2013年1月22日电子出版)。
白介素2 (IL-2)由T细胞产生。其为调节T细胞亚群的生长因子。其也是调节免疫反应的重要因子。其可以促进和活化B细胞的扩增,并涉及抗体反应、造血和肿瘤监测。重组人IL-2已被美国FDA批准用于治疗恶性肿瘤(包括黑色素瘤、肾肿瘤等)。其也在治疗慢性病毒感染的临床研究下(Pharmacologic administration of interleukin-2. Chavez,A.R., 等人, Ann N Y Acad Sci, 2009. 1182: 14-27)。在体外实验中,CTLA4 mAb可以特异性减轻CTLA4对机体的免疫抑制,活化T细胞,并诱导IL-2产生,且因此在针对肿瘤的基因疗法等中具有广阔的前景。
作为影响T细胞的功能的重要因子,CTLA4和CTLA4 mAb可以通过干扰体内的免疫微环境对疾病产生特定的治疗效果。它们具有高效力,并且补救传统药物的缺陷,开辟了一条基因疗法的新型途径。CTLA4和CTLA4 mAb正在实验和临床试验的各个阶段中进行测试。例如,在自身免疫性疾病中,它们有效地抑制哮喘的动物模型中的气道高反应性,防止风湿性疾病的发展,介导对体内同种异体移植物的免疫耐受性等。另一方面,尽管生物基因疗法在短期临床试验中没有显示任何不良影响,但应当注意长期应用之后的潜在影响。例如,CTLA4 mAb对CTLA4-B7信号传导的过度阻断可以导致自身免疫性疾病的发展。由于抗体可以特异性结合其抗原并诱导靶细胞的裂解或阻断病理学的进展,基于抗体、尤其是人源化抗体的药物的开发和利用在临床治疗人类中的恶性肿瘤和其他免疫疾病中具有重要意义。
发明概述
本发明人鉴定了杂交瘤细胞系LT002 (CTLA4-4G10),并将其在2015年6月16日以保藏号CCTCC NO:C201587保藏于中国典型培养物保藏中心(CCTCC)。本发明人令人惊讶地发现:杂交瘤细胞系LT002能够分泌和产生特异性结合CTLA4的特异性单克隆抗体(命名为4G10),并且所述单克隆抗体可以非常有效地阻断CTLA4与B7的结合。此外,本发明人生成各种抗CTLA4人源化抗体,包括命名为4G10H1L1、4G10H3L3、4G10H4L3和4G10H5L3的抗体。
因此,提供了以下发明。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含:
· 包含SEQ ID NO:21或SEQ ID NO:27的氨基酸序列的HCDR1,
· 包含SEQ ID NO:22或SEQ ID NO:28的氨基酸序列的HCDR2,和
· 包含SEQ ID NO:23或SEQ ID NO:29的氨基酸序列的HCDR3;
和/或所述轻链可变区包含:
· 包含SEQ ID NO:24或SEQ ID NO:30的氨基酸序列的LCDR1,
· 包含SEQ ID NO:25或SEQ ID NO:31的氨基酸序列的LCDR2,和
· 包含SEQ ID NO:26或SEQ ID NO:32的氨基酸序列的LCDR3。
在一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:21的氨基酸序列的HCDR1,包含SEQ ID NO:22的氨基酸序列的HCDR2,和包含SEQID NO:23的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:24的氨基酸序列的LCDR1,包含SEQ ID NO:25的氨基酸序列的LCDR2,和包含SEQ ID NO:26的氨基酸序列的LCDR3。
在另一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:21(其中X1 = M)的氨基酸序列的HCDR1,包含SEQ ID NO:22 (其中X1 = N或D,X2 = T或D,X3 = A且X4=Q)的氨基酸序列的HCDR2,和包含SEQ ID NO:23的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:24(其中X1 = P)的氨基酸序列的LCDR1,包含SEQ ID NO:25(其中X1 = K且X2 =S)的氨基酸序列的LCDR2,和包含SEQ ID NO:26(其中X1 = W且X2 = W)的氨基酸序列的LCDR3。在另一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:21(其中X1 = M)的氨基酸序列的HCDR1,包含SEQ ID NO:22 (其中X1 = N,X2 = T,X3 = A且X4=Q)的氨基酸序列的HCDR2,和包含SEQ IDNO:23的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:24(其中X1 = P)的氨基酸序列的LCDR1,包含SEQ ID NO:25(其中X1 = K且X2 =S)的氨基酸序列的LCDR2,和包含SEQ ID NO:26(其中X1 = W且X2 = W)的氨基酸序列的LCDR3。在另一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:27的氨基酸序列的HCDR1,包含SEQ ID NO:28的氨基酸序列的HCDR2,和包含SEQ ID NO:29的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:30的氨基酸序列的LCDR1,包含SEQ IDNO:31的氨基酸序列的LCDR2,和包含SEQ ID NO:32的氨基酸序列的LCDR3。在另一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:27的氨基酸序列的HCDR1,包含SEQ ID NO:28 (其中X1 = N或D,X2 = T或D)的氨基酸序列的HCDR2,和包含SEQ ID NO:29的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:30的氨基酸序列的LCDR1,包含SEQ ID NO:31的氨基酸序列的LCDR2,和包含SEQ ID NO:32(其中X1= W且X2 = W)的氨基酸序列的LCDR3。在另一个实施方案中,所述抗体或其抗原结合片段包含:重链可变区,其包含:包含SEQ ID NO:27的氨基酸序列的HCDR1,包含SEQ ID NO:28(其中X1 = N,X2 = T)的氨基酸序列的HCDR2,和包含SEQ ID NO:29的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:30的氨基酸序列的LCDR1,包含SEQ ID NO:31的氨基酸序列的LCDR2,和包含SEQ ID NO:32(其中X1 = W且X2 = W)的氨基酸序列的LCDR3。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:4。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述轻链可变区包含SEQ ID NO:6。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQID NO:4且所述轻链可变区包含SEQ ID NO:6。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区与SEQ ID NO:4具有至少90%、95%、96%、97%、98%或99%同一性和/或所述轻链可变区与SEQID NO:6具有至少90%、95%、96%、97%、98%或99%同一性。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区在SEQ ID NO:4的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或所述轻链可变区在SEQ ID NO:6的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代。在一些实施方案中,SEQ ID NO:4或SEQ ID NO:6中的序列变异或氨基酸取代发生在SEQ ID NO:27-32中鉴定的CDR区之外。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:8。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述轻链可变区包含SEQ ID NO:10。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:8且所述轻链可变区包含SEQ ID NO:10。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区与SEQ ID NO:8具有至少90%、95%、96%、97%、98%或99%同一性和/或所述轻链可变区与SEQ ID NO:10具有至少90%、95%、96%、97%、98%或99%同一性。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区在SEQ ID NO:8的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或所述轻链可变区在SEQ ID NO:10的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代。在一些实施方案中,SEQ ID NO:8或SEQ ID NO:10中的序列变异或氨基酸取代发生在SEQ ID NO:27-32中鉴定的CDR区之外。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:12。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述轻链可变区包含SEQ ID NO:14。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:12且所述轻链可变区包含SEQ ID NO:14。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区与SEQ ID NO:12具有至少90%、95%、96%、97%、98%或99%同一性和/或所述轻链可变区与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区在SEQ ID NO:12的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或所述轻链可变区在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代。在一些实施方案中,SEQ ID NO:12或SEQ ID NO:14中的序列变异或氨基酸取代发生在SEQ ID NO:27-32中鉴定的CDR区之外。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:16。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:16且所述轻链可变区包含SEQ ID NO:14。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区与SEQ ID NO:16具有至少90%、95%、96%、97%、98%或99%同一性和/或所述轻链可变区与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区在SEQ ID NO:16的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或所述轻链可变区在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代。在一些实施方案中,SEQ ID NO:16或SEQ ID NO:14中的序列变异或氨基酸取代发生在SEQ ID NO:27-32中鉴定的CDR区之外。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:18。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:18且所述轻链可变区包含SEQ ID NO:14。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区与SEQ ID NO:18具有至少90%、95%、96%、97%、98%或99%同一性和/或所述轻链可变区与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性。在一个实施方案中,本发明包括结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区在SEQ ID NO:18的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或所述轻链可变区在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代。在一些实施方案中,SEQ ID NO:18或SEQ ID NO:14中的序列变异或氨基酸取代发生在SEQ ID NO:27-32中鉴定的CDR区之外。在一个实施方案中,所述抗体或其抗原结合片段是包含两条重链和两条轻链的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG2恒定结构域的人源化抗体。在一个实施方案中,所述抗体或其抗原结合片段是包含人IgG4恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段是包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。在另一个实施方案中,所述抗体或其抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)或双抗体。
在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述重链可变区包含SEQ ID NO:19。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中所述轻链可变区包含SEQ ID NO:20。在一个实施方案中,本发明提供了结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和轻链可变区,其中所述重链可变区包含SEQ ID NO:19且所述轻链可变区包含SEQ ID NO:20。
在一个实施方案中,本发明的抗体或抗原结合片段(如上所述)是分离的。
在一个实施方案中,本发明的抗体或抗原结合片段(如上所述)是在CHO细胞中产生的抗体。
在一个实施方案中,本发明的抗体或抗原结合片段(如上所述)以小于约10-5 M,例如,小于约10-6 M、10-7 M、10-8 M、10-9 M、10-10 M或更小的KD结合人CTLA4,如通过表面等离振子共振(例如,BIACORE)或类似技术(例如KinExa或OCTET)所测定。在一个实施方案中,上述抗体或抗原结合片段以约1 x 10-9 M至约1 x 10-12 M的KD结合人CTLA4,如通过表面等离振子共振(例如,BIACORE)或类似技术(例如KinExa或OCTET)所测定。
在一个实施方案中,本发明的抗体或其抗原结合片段(如上所述)任选地具有以下特征中的至少一种:检测样品中CTLA4的水平,与食蟹猴CTLA4交叉反应,阻断CTLA4与B7的结合,调节(例如,下调)CTLA4的活性或CTLA4的水平,减轻CTLA4对机体的免疫抑制,活化T淋巴细胞,增加T淋巴细胞中IL-2的表达;和/或增加T淋巴细胞中IFN-γ的表达。
在一个实施方案中,本发明涉及在2015年6月16日以保藏号CCTCC C201587保藏于中国典型培养物保藏中心(CCTCC)的杂交瘤细胞系LT002。
在一个实施方案中,本发明涉及由在2015年6月16日以保藏号CCTCC C201587保藏于中国典型培养物保藏中心(CCTCC)的杂交瘤细胞系LT002产生的单克隆抗体。
本发明还涉及分离的多肽,其包含SEQ ID NO:4、6、8、10、12、14、16、18、19或20中任一个的氨基酸序列。
本发明还涉及药物组合物,其包含本发明的抗体或抗原结合片段中的任一种。在一个实施方案中,本发明包括本发明的抗体或抗原结合片段中的任一种,并且进一步包括药学上可接受的载体和/或赋形剂。在一个实施方案中,本发明包括本发明的抗体或抗原结合片段中的任一种,并且进一步包含第二治疗剂。所述第二治疗剂可以选自:抗PD1抗体或其抗原结合片段;抗LAG3抗体或其抗原结合片段;抗VISTA抗体或其抗原结合片段;抗TIGIT抗体或其抗原结合片段;抗TIM3抗体或其抗原结合片段;抗HVEM抗体或其抗原结合片段;抗CD27抗体或其抗原结合片段;抗CD137抗体或其抗原结合片段;抗OX40抗体或其抗原结合片段;抗CD28抗体或其抗原结合片段;抗PDL1抗体或其抗原结合片段;抗PDL2抗体或其抗原结合片段;抗GITR抗体或其抗原结合片段;抗ICOS抗体或其抗原结合片段;抗SIRPα抗体或其抗原结合片段;抗ILT2抗体或其抗原结合片段;抗ILT3抗体或其抗原结合片段;抗ILT4抗体或其抗原结合片段;和抗ILT5抗体或其抗原结合片段;抗CD73抗体或其抗原结合片段;和抗CD47抗体或其抗原结合片段。在一个实施方案中,所述抗PD1抗体或其抗原结合片段选自:派姆单抗或其抗原结合片段和尼沃单抗或其抗原结合片段。
本发明还包括缀合物,其包含根据本发明的抗体或其抗原结合片段和缀合的部分。在一个实施方案中,所述缀合的部分是可检测的标记物。在一个实施方案中,所述缀合的部分是放射性同位素、荧光物质、发光物质、生色物质或酶。
本发明还包括试剂盒,其包含根据本发明的抗体或其抗原结合片段,或根据本发明的缀合物和特异性识别所述抗体或其抗原结合片段的第二抗体。在一个实施方案中,所述第二抗体进一步包含可检测的标记物,例如放射性同位素、荧光物质、发光物质、生色物质或酶。
本发明还包括编码本发明的抗体或抗原结合片段或本发明的多肽的核酸分子。在一个实施方案中,本发明包括SEQ ID NO:3的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:5的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:7的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:9的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:11的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:13的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:15的核酸序列。在另一个实施方案中,本发明包括SEQ ID NO:17的核酸序列。本发明还包括包含本发明的核酸的载体,和包含本发明的核酸或载体的宿主细胞。
本发明还包括产生抗体或抗原结合片段的方法,其包括:(i)在有利于表达编码本发明的抗体或抗原结合片段中的任一种的重链和/或轻链的多核苷酸的条件下,培养包含所述多核苷酸的宿主细胞;和(ii)任选地,从所述宿主细胞和/或培养基回收所述抗体或抗原结合片段。
本发明还包括治疗人个体中的癌症的方法,其包括向所述个体施用有效量的本发明的抗体或抗原结合片段,其任选地与另外的治疗剂或治疗程序联合。所述另外的治疗剂可以选自:抗PD1抗体或其抗原结合片段;抗LAG3抗体或其抗原结合片段;抗VISTA抗体或其抗原结合片段;抗TIGIT抗体或其抗原结合片段;抗TIM3抗体或其抗原结合片段;抗HVEM抗体或其抗原结合片段;抗CD27抗体或其抗原结合片段;抗CD137抗体或其抗原结合片段;抗OX40抗体或其抗原结合片段;抗CD28抗体或其抗原结合片段;抗PDL1抗体或其抗原结合片段;抗PDL2抗体或其抗原结合片段;抗GITR抗体或其抗原结合片段;抗ICOS抗体或其抗原结合片段;抗SIRPα抗体或其抗原结合片段;抗ILT2抗体或其抗原结合片段;抗ILT3抗体或其抗原结合片段;抗ILT4抗体或其抗原结合片段;抗ILT5抗体或其抗原结合片段;抗CD73抗体或其抗原结合片段;和抗CD47抗体或其抗原结合片段。在一个实施方案中,所述抗PD1抗体或其抗原结合片段选自:派姆单抗或其抗原结合片段和尼沃单抗或其抗原结合片段。
本发明还包括治疗人个体中的感染或感染性疾病的方法,其包括向所述个体施用有效量的本发明的抗体或抗原结合片段,其任选地与另外的治疗剂或治疗程序联合。所述另外的治疗剂可以选自:抗PD1抗体或其抗原结合片段;抗LAG3抗体或其抗原结合片段;抗VISTA抗体或其抗原结合片段;抗TIGIT抗体或其抗原结合片段;抗TIM3抗体或其抗原结合片段;抗HVEM抗体或其抗原结合片段;抗CD27抗体或其抗原结合片段;抗CD137抗体或其抗原结合片段;抗OX40抗体或其抗原结合片段;抗CD28抗体或其抗原结合片段;抗PDL1抗体或其抗原结合片段;抗PDL2抗体或其抗原结合片段;抗GITR抗体或其抗原结合片段;抗ICOS抗体或其抗原结合片段;抗SIRPα抗体或其抗原结合片段;抗ILT2抗体或其抗原结合片段;抗ILT3抗体或其抗原结合片段;抗ILT4抗体或其抗原结合片段;抗ILT5抗体或其抗原结合片段;抗CD73抗体或其抗原结合片段;和抗CD47抗体或其抗原结合片段。在一个实施方案中,所述抗PD1抗体或其抗原结合片段选自:派姆单抗或其抗原结合片段和尼沃单抗或其抗原结合片段。
本发明还包括疫苗,其包含本发明的抗体或抗原结合片段和抗原。
本发明还包括用于检测样品中的CTLA4肽或其片段的存在的方法,其包括使所述样品与本发明的抗体或抗原结合片段接触,和检测所述抗体或片段和所述肽之间的复合物的存在;其中所述复合物的检测表明CTLA4肽的存在。
本发明还包括增加免疫细胞的活性的方法,其包括使所述免疫细胞与本发明的抗体或抗原结合片段中的任一种接触。
在一个实施方案中,本发明包括增加免疫细胞的活性的方法,其包括向有需要的个体施用有效量的本发明的抗体或抗原结合片段。在一个实施方案中,所述方法用于:治疗癌症;治疗感染或感染性疾病;或作为疫苗佐剂。
在一个实施方案中,本发明包括本发明的抗体或抗原结合片段用于制备药物的用途,所述药物:增加免疫细胞活化;治疗癌症;或治疗感染或感染性疾病。
在一个实施方案中,本发明包括本发明的抗体或抗原结合片段用于制备用于治疗癌症的药物的用途,所述药物用于:增加免疫细胞活化;治疗癌症;或治疗感染或感染性疾病。
本发明的一个进一步方面涉及根据本发明的任一个实施方案的抗体或其抗原结合片段在制备用于检测样品中的CTLA4的存在或水平的试剂盒中的用途。
本发明的一个进一步方面涉及根据本发明的任一个实施方案的抗体或其抗原结合片段或根据本发明的缀合物在制备药物中的用途,所述药物用于肿瘤、癌症、贫血、感染或感染性疾病的预防和/或治疗和/或辅助疗法和/或诊断。
本发明的一个进一步方面涉及根据本发明的任一个实施方案的抗体或其抗原结合片段或根据本发明的缀合物在制备药剂中的用途,所述药剂:
· 检测样品中CTLA4的水平,
· 阻断CTLA4与B7的结合,
· 调节(例如,下调)CTLA4的活性或CTLA4的水平,
· 减轻CTLA4对机体的免疫抑制,
· 活化T淋巴细胞,
· 增加T淋巴细胞中IL-2的表达;
· 增加T淋巴细胞中IFN-γ的表达;和/或
· 与食蟹猴CTLA4交叉反应。
本发明的一个进一步方面涉及体内或体外方法,其包括向细胞施用有效量的根据本发明的任一个实施方案的抗体或其抗原结合片段或根据本发明的缀合物的步骤,其中所述方法选自以下:
· 检测样品中CTLA4的水平的方法,
· 阻断CTLA4与B7的结合的方法,
· 调节(例如,下调)CTLA4的活性或CTLA4的水平的方法,
· 减轻CTLA4对机体的免疫抑制的方法,
· 活化T淋巴细胞的方法,
· 增加T淋巴细胞中IL-2的表达的方法;和/或
· 增加T淋巴细胞中IFN-γ的表达的方法。
本发明的一个进一步方面涉及肿瘤或癌症的预防和/或治疗和/或辅助疗法和/或诊断的方法,其包括向个体施用有效量的根据本发明的任一个实施方案的抗体或其抗原结合片段或根据本发明的缀合物。
根据本发明的任一个实施方案的抗体或其抗原结合片段,其用于肿瘤或癌症的预防和/或治疗和/或辅助疗法和/或诊断。
根据本发明的任一个实施方案的抗体或其抗原结合片段,其用于:
· 阻断CTLA4与B7的结合,
· 调节(例如,下调)CTLA4的活性或CTLA4的水平,
· 减轻CTLA4对机体的免疫抑制,
· 活化T淋巴细胞,
· 增加T淋巴细胞中IL-2的表达;和/或
· 增加T淋巴细胞中IFN-γ的表达。
附图简述
图1显示CTLA4-mFc融合蛋白的SDS-PAGE结果。4个泳道中的样品和上样量从左到右为:标记物,10μL;CTLA4-mFc融合蛋白,1μg;CTLA4-mFc融合蛋白,2μg;CTLA4-mFc融合蛋白,3μg。
图2显示测定4G10抗体的动态特征参数的结果。
图3显示测定4G10H1L1抗体的动态特征参数的结果。
图4显示测定4G10H3L3抗体的动态特征参数的结果。
图5显示使用间接ELISA测定抗体4G10H1L1和4G10H3L3与CTLA4抗原的结合。
图6显示使用竞争ELISA测定抗体4G10H1L1和4G10H3L3与B7竞争结合CTLA4抗原的活性。
图7显示抗体4G10H1L1与293T-CTLA4细胞表面上的蛋白CTLA4的结合的EC50。MFI代表平均荧光强度。
图8显示抗体4G10H3L3与293T-CTLA4细胞表面上的蛋白CTLA4的结合的EC50。
图9显示抗体4G10H3L3与T细胞表面上的抗原CTLA4结合的活性。
图10显示抗体4G10H1L1和4G10H3L3对混合淋巴细胞中细胞因子IFN-γ的分泌的影响。
图11显示抗体4G10H1L1和4G10H3L3对混合淋巴细胞中细胞因子IL-2的分泌的影响。
图12显示结合食蟹猴CTLA-4的抗体4G103L3的结合。
详述
除非另有说明,否则本文使用的科学和技术术语具有本领域技术人员所通常理解的含义。并且,本文使用的细胞培养、分子遗传学、核酸化学、免疫学的程序是相关领域内广泛利用的方法。为了更好地理解本发明的目的,下面提供相关术语的定义和解释。
如本文所用,当提及CTLA4蛋白(细胞毒性T淋巴细胞抗原4)的氨基酸序列时,其包括CTLA4蛋白的全长,或者CTLA4的细胞外片段CTLA4ECD (SEQ ID NO:1的用波浪线加下划线的部分)或者包含CTLA4ECD的片段;还包括CTLA4ECD的融合蛋白,例如与小鼠或人IgG的Fc蛋白片段(mFc或hFc)融合的CTLA4ECD片段(参见实施例1中的描述)。然而,如本领域技术人员所理解,在CTLA4蛋白的氨基酸序列中,可天然产生或人工引入突变或变异(包括且不限于取代、缺失和/或添加),而不影响其生物学功能。因此,在本发明中,术语“CTLA4蛋白”应包括所有此类序列,包括SEQ ID NO:1的用波浪线加下划线的部分的序列以及其天然或人工的变体。并且,当提及CTLA4蛋白的序列片段时,其不仅包括SEQ ID NO:1的用波浪线加下划线的部分的序列片段,而且还包括其天然或人工变体的相应序列片段。
如本文所用,除非具体说明,所述B7是指B7-1和/或B7-2;且其特定蛋白序列是指本领域中已知的序列。可以参考现有技术的文献或GenBank中公开的序列,例如,B7-1(CD80, NCBI基因ID: 941),B7-2 (CD86, NCBI基因ID: 942)。
如本文所用,术语EC50是指50%最大效应的浓度,即,引起50%最大效应的浓度。
如本文所用,术语“抗体”是指通常由两对多肽链(每对具有“轻”(L)链和“重”(H)链)组成的免疫球蛋白分子。抗体轻链可分类为κ和λ轻链。重链可分类为μ、δ、γ、α或ε,并且分别将抗体的同种型定义为IgM、IgD、IgG、IgA和IgE。在轻链和重链内,可变区和恒定区经由约12或更多个氨基酸的“J”区连接,且重链还包含约3个或更多个氨基酸的“D”区。各重链由重链可变区(VH)和重链恒定区(CH)组成。重链恒定区由3个结构域(CH1、CH2和CH3)组成。各轻链由轻链可变区(VL)和轻链恒定区(CL)组成。轻链恒定区由CL结构域组成。抗体的恒定区可介导免疫球蛋白与宿主组织或因子,包括免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一组分(C1q)的结合。VH和VL区还可被细分为具有高变性的区域(称为互补决定区(CDR)),其散布有相对保守的称为构架区(FR)的区域。各VH和VL由按下列顺序从氨基末端至羧基末端排列的3个CDR和4个FR组成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。各对重链/轻链的可变区(VH和VL)分别形成抗体结合位点。氨基酸至各区域或结构域的分配遵循Kabat, Sequences of Proteins of Immunological Interest (National Institutesof Health, Bethesda, Md. (1987和1991))或Chothia & Lesk (1987) J. Mol. Biol.196:901-917; Chothia等人(1989) Nature 342:878-883中提供的定义。术语“抗体”不受任何特定的产生抗体的方法限制。例如,其包括,特别地,重组抗体、单克隆抗体和多克隆抗体。抗体可以是不同同种型的抗体,例如,IgG(例如,IgG1,IgG2,IgG3或IgG4亚型),IgA1,IgA2,IgD,IgE或IgM抗体。
如本文所用,术语抗体的“抗原结合片段”是指包含全长抗体的片段的多肽,其保留特异性结合全长抗体所结合的抗原和/或与全长抗体竞争特异性结合抗原的能力。其也被称为“抗原结合部分”。通常参见,Fundamental Immunology, Ch. 7 (Paul, W., 编, 第二版, Raven Press, N.Y. (1989)),其以其整体通过引用并入本文用于所有目的。可通过重组DNA技术或完整抗体的酶促或化学裂解来产生抗体的抗原结合片段。在一些情况下,抗原结合片段包括Fab、Fab'、F(ab')2、Fd、Fv、dAb和互补决定区(CDR)片段、单链抗体(例如,scFv)、嵌合抗体、双抗体(diabody)和此类多肽,其包含足以为多肽赋予特异性抗原结合的能力的抗体的至少一部分。
如本文所用,术语“Fd片段”是指由VH和CH1结构域组成的抗体片段;术语“Fv片段”是指由抗体的单臂的VL和VH结构域组成的抗体片段;术语“dAb片段”是指由VH结构域组成的抗体片段(Ward等人, Nature 341:544-546 (1989));术语“Fab片段”是指由VL、VH、CL和CH1结构域组成的抗体片段;且术语“F(ab′)2片段”是指包含通过铰链区上的二硫桥连接的两个Fab片段的抗体片段。
在一些情况下,抗体的抗原结合片段是单链抗体(例如,scFv),其中VL和VH结构域经由使得能够产生单个多肽链的接头与彼此配对以形成单价分子(参见,例如,Bird等人,Science 242:423-426 (1988)和Huston等人, Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988))。此类scFv分子可具有一般结构:NH2-VL-接头-VH-COOH或NH2-VH-接头-VL-COOH。来自现有技术的合适的接头由重复的GGGGS氨基酸序列或其变体组成。例如,可使用具有氨基酸序列(GGGGS)4的接头,但也可使用其变体(Holliger等人 (1993)Proc. Natl.Acad. Sci. USA 90: 6444-6448)。可用于本发明中的其他接头由Alfthan等人 (1995)Protein Eng. 8:725-731; Choi等人 (2001) Eur. J. Immunol. 31: 94-106; Hu等人(1996) Cancer Res. 56:3055-3061; Kipriyanov等人 (1999) J. Mol. Biol. 293:41-56和Roovers等人 (2001) Cancer Immunol.描述。
在一些情况下,抗体的抗原结合片段是双抗体(二价抗体),其中VH和VL结构域在单个多肽链上表达。然而,采用的接头太短以致相同链上的两个结构域不能与彼此配对,且迫使所述结构域与另一条链上的互补结构域配对。通过这种方式,形成两个抗原结合位点(参见,例如,Holliger P.等人, Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)和Poljak R. J.等人, Structure 2:1121-1123 (1994))。
可使用本领域技术人员已知的常规技术(例如,重组DNA技术或酶促或化学裂解方法)从给定的抗体获得抗体的抗原结合片段(例如,上述抗体片段),并且以与用于完整抗体的方式相同的方式针对特异性进行筛选。
在本文中,除非上下文明确指出,否则当提及术语“抗体”时,其不仅包括完整抗体,而且还包括抗体的抗原结合片段。
如本文所用,术语“mAb”和“单克隆抗体”是指,来自高度同源的抗体分子的群体的抗体或抗体片断,即除可能天然存在的自然突变外,构成所述群体的个别抗体是相同的。单克隆抗体对抗原上的单一表位是高度特异性的。与单克隆抗体相比,多克隆抗体制剂通常包括至少2种或更多种不同的识别抗原上的不同表位的抗体。单克隆抗体通常可使用Kohler等人(Nature, 256:495,1975)首次描述的杂交瘤技术获得,或者可使用重组DNA技术获得(例如,参见美国专利4,816,567)。
如本文所用,术语“嵌合”抗体是指此类抗体,其中轻链或/和重链的一部分源自抗体(其可以源自特定物种或属于特定抗体类别或亚类),而轻链或/和重链的另一部分源自另一抗体(其可以源自相同或不同的物种或属于相同或不同的抗体类别或亚类),只要其保留结合靶抗原的活性(授予Cabilly等人的US 4,816,567; Morrison等人, Proc. Natl.Acad. Sci. USA, 81:6851-6855 (1984))。
如本文所用,术语“人源化”抗体是指人免疫球蛋白(受体抗体)的全部或一些CDR被非人抗体(供体抗体)的CDR替换后获得的抗体或抗体片段,其中供体抗体可以是具有期望的特异性、亲和力或反应性的非人(例如,小鼠、大鼠或兔)抗体。此外,受体抗体的构架区(FR)的一些氨基酸残基可被相应的非人抗体的氨基酸残基或其他抗体的氨基酸残基替换,以便进一步改善或优化抗体的性能。对于关于人源化抗体的更多详情,参见例如,Jones等人, Nature, 321:522-525 (1986); Reichmann等人, Nature, 332:323-329 (1988);Presta, Curr. Op. Struct. Biol., 2:593-596 (1992); 和Clark, Immunol. Today21: 397-402 (2000)。
如本文所用,术语“表位”是指抗原上被免疫球蛋白或抗体特异性结合的部分。在本领域中,“表位”也称为“抗原决定簇”。表位或抗原决定簇通常由分子的活性表面基团、例如氨基酸或碳水化合物或糖侧链组成,并且通常具有特定的三维结构特征以及特定的电荷特征。例如,表位通常以距离空间构象包含至少3、4、5、6、7、8、9、10、11、12、13、14或15个连续或非连续的氨基酸。其可以是“线性的”或“构象的”表位。参见,例如,Epitope MappingProtocols in Methods in Molecular Biology, Vol. 66, G. E. Morris, 编(1996)。在线性表位中,蛋白和相互作用分子(例如抗体)之间的所有相互作用点沿着蛋白的一级氨基酸序列线性存在。在构象表位中,相互作用点跨越与彼此分开的蛋白的氨基酸残基而存在。
本发明包括分离的抗CTLA4抗体和其抗原结合片段和其使用方法。“分离的”抗体或其抗原结合片段至少部分不含来自产生其的细胞或细胞培养物的其他生物分子。此类生物分子包括核酸、蛋白、脂质、碳水化合物或其他物质,诸如细胞碎片和生长培养基。分离的抗体或抗原结合片段可进一步至少部分不含表达系统组分,诸如来自宿主细胞或其生长培养基的生物分子。通常,术语“分离的”不意指完全不存在此类生物分子或不存在水、缓冲剂或盐,或包括抗体或片段的药物制剂的组分。
“分离的核酸分子”或“分离的多核苷酸”意指基因组、mRNA、cDNA或合成来源的DNA或RNA或其一定组合,其不与其中在自然界中发现分离的多核苷酸的多核苷酸的全部或一部分缔合,或连接至其在自然界中不连接的多核苷酸。出于本发明的目的,应理解“包含特定核苷酸序列的核酸分子”不涵盖完整染色体。除指定序列之外,“包含”指定核酸序列的分离的核酸分子可包括最多达十种或甚至最多达二十种或更多种其他蛋白或其部分或片段的编码序列,或可包括控制所述核酸序列的编码区域的表达的可操作连接的调节序列,和/或可包括载体序列。
如本文所用,术语“大肠杆菌表达系统”是指由大肠杆菌(菌株)和载体组成的表达系统,其中大肠杆菌(菌株)来源于商业可得的菌株,例如但不限于:GI698、ER2566、BL21(DE3)、B834(DE3)和BLR(DE3)。
如本文所用,术语“载体”是指可将多核苷酸插入其中的携带核酸的工具。当载体使得能够表达插入的多核苷酸编码的蛋白时,载体被称为表达载体。载体可以通过转化、转导或转染引入宿主细胞,使得所述载体携带的遗传物质组分在宿主细胞中表达。载体是本领域技术人员众所周知的,包括但不限于:质粒;噬菌粒;粘粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC);噬菌体,例如λ噬菌体或M13噬菌体以及动物病毒等。可用作载体的动物病毒包括但不限于,逆转录病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(例如,单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(例如,SV40)。载体可以包含几个用于控制表达的组分,包括但不限于,启动子序列、转录起始序列、增强子序列、选择组分和报告基因。另外,载体还可包含复制起始位点。
如本文所用,术语“宿主细胞”是指可用于引入载体的细胞,包括但不限于,原核细胞诸如大肠杆菌或枯草芽孢杆菌,真菌细胞诸如酵母细胞或曲霉菌,昆虫细胞诸如S2果蝇细胞或Sf9,或动物细胞诸如成纤维细胞、CHO细胞、COS细胞、NSO细胞、HeLa细胞、BHK细胞、HEK293细胞或人细胞。
如本文所用,术语“同一性”用于描述两个多肽之间或两个核酸之间的序列匹配。当两个进行比较的序列中的相应位置被相同的碱基或氨基酸单体亚单元占据(例如,两个DNA分子中的相应位置都被腺嘌呤占据,或两个多肽中的相应位置都被赖氨酸占据)时,所述分子在该位置处是相同的。两个序列之间的“百分比同一性”是由这两个序列共有的匹配位置数目除以进行比较的位置数目×100的函数。例如,如果两个序列的10个位置中的6个匹配,则这两个序列具有60%同一性。例如,DNA序列CTGACT和CAGGTT共有50%同一性(总共6个位置中有3个位置匹配)。通常,将两个序列在比对之后进行比较以生成最大同一性。例如,这种比对可使用计算机程序例如Align程序(DNAstar,Inc.)通过Needleman等人(1970) J. Mol. Biol. 48: 443-453的方法来方便地实现。此外,可使用并入ALIGN程序(版本2.0)的E. Meyers和W. Miller (Comput. Appl Biosci., 4:11-17 (1988))的算法,使用PAM120权重残基表、12的缺口长度罚分和4的缺口罚分来测定两个氨基酸序列之间的百分比同一性。此外,可使用并入GCG软件包(在www.gcg.com可得)的GAP程序的Needleman和Wunsch (J MoI Biol. 48:444-453 (1970))的算法,使用Blossum62矩阵或PAM250矩阵、16、14、12、10、8、6或4的缺口权重和1、2、3、4、5或6的长度权重来测定两个氨基酸序列之间的百分比同一性。
如本文所用,术语“特异性结合”是指两个分子之间的非随机结合反应,诸如抗体和其靶向的抗原之间的反应。在一些实施方案中,特异性结合某原的抗体(或对抗原特异性的抗体)意味着,抗体以小于约10-5M,例如小于约10-6M、10-7M、10-8M、10-9M或10-10M或更小的亲和力(KD)结合该抗原。
如本文所用,术语“KD”是指特定抗体-抗原相互作用的解离平衡,其用于描述抗体和抗原之间的结合亲和力。平衡解离常数越小,抗体-抗原结合越紧密,并且抗体和抗原之间的亲和力越高。通常,抗体以小于约10-5M,例如小于约10-6M、10-7M、10-8M、10-9M或10-10M或更小的解离平衡常数(KD)结合抗原,例如,如使用BIACORE仪器上的表面等离振子共振(SPR)或类似技术(例如,OCTET或KINEXA)所测定。
如本文所用,术语“单克隆抗体”和“mAb”具有相同的含义且可互换使用。此外,术语“多克隆抗体”和“pub”具有相同的含义且可互换使用。再次,术语“多肽”和“蛋白”具有相同的含义且可互换使用。并且,在本发明中,氨基酸通常通过本领域众所周知的单字母和三字母缩写来表示。例如,丙氨酸可通过A或Ala表示。
如本文所用,术语“杂交瘤”和“杂交瘤细胞系”可互换使用。而且,当提及术语“杂交瘤”和“杂交瘤细胞系”时,其还包括杂交瘤的亚克隆和后代细胞。例如,当提及杂交瘤细胞系LT002或LT003时,其还包括杂交瘤细胞系LT002或LT003的亚克隆和后代细胞。
如本文所用,术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与个体和活性组分相容的载体和/或赋形剂,其是本领域众所周知的(参见例如Remington's Pharmaceutical Sciences. 由Gennaro AR编辑, 第19版 Pennsylvania:Mack Publishing Company, 1995),并且包括但不限于:pH调节剂,表面活性剂,佐剂,离子强度增强剂。例如,pH调节剂包括但不限于磷酸盐缓冲液;表面活性剂包括但不限于阳离子、阴离子或非离子型表面活性剂,例如Tween-80;并且离子强度增强剂包括但不限于氯化钠。
如本文所用,术语“佐剂”是指非特异性免疫增强剂,其当与抗原一起或预先递送入机体时可增强机体对抗原的免疫应答或改变免疫应答的类型。存在许多佐剂,包括但不限于铝佐剂(例如氢氧化铝)、弗氏佐剂(例如完全弗氏佐剂和不完全弗氏佐剂)、短小棒状杆菌、脂多糖、细胞因子等。弗氏佐剂是目前动物实验中最常用的佐剂,并且氢氧化铝佐剂是临床试验中广泛使用的佐剂。
如本文所用,术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如,针对疾病(例如与过度的CTLA4与B7结合或CTLA4活性相关的疾病或肿瘤)的预防有效量是指足以预防、阻止或延迟疾病(例如与过度的CTLA4与B7结合或CTLA4活性相关的疾病或肿瘤)的发展的量;并且针对疾病的治疗有效量是指足以治愈或至少部分阻止患有疾病的患者中的疾病和其并发症的量。确定这种有效量完全在本领域技术人员的技能范围之内。例如,治疗有效量将取决于待治疗的疾病的严重程度,患者的免疫系统的总体状态,患者的总体状态,例如患者的年龄、体重和性别,药剂的施用模式,同时施用的其他疗法等。
除非上下文另外清楚地规定,否则如本文(包括随附权利要求)所用,词语的单数形式诸如“一个/种(a)”、“一个/种(an)”和“该(the)”包括其对应的复数个提及物。
“施用”在应用于动物、人类、实验个体、细胞、组织、器官或生物流体时是指外源性药物、治疗剂、诊断剂或组合物与所述动物、人类、个体、细胞、组织、器官或生物流体接触。
“治疗(Treat)”或“治疗(treating)”意指在内部或外部向具有一种或多种疾病症状或怀疑患有疾病的药剂对其具有治疗活性的个体或患者施用治疗剂,诸如含有本发明的任一抗体或抗原结合片段的组合物。通常,药剂以有效缓解所治疗个体或群体中的一种或多种疾病症状的量施用,无论是通过任何临床上可测量的程度诱导此类症状的消退还是通过任何临床上可测量的程度抑制其进展。有效缓解任何特定疾病症状的治疗剂的量可根据因素诸如患者的疾病状态、年龄和体重以及药物在个体中引发所需反应的能力而变化。是否已缓解疾病症状可通过医师或其他熟练医疗护理提供者通常用于评价该症状的严重程度或进展状态的任何临床测量来评价。
本发明的抗体
治疗性抗体,尤其是单克隆抗体(MAB)在治疗几种疾病方面已取得优异的效力。获得这种治疗性抗体的传统方法是用抗原免疫动物,从免疫的动物获得针对抗原的抗体,任选地,通过亲和力成熟改善对抗原具有低亲和力的抗体。然而,这种方法是耗时且耗力的,并且经常不能靶向抗原上的特定表位。
抗原结合依赖于轻链和重链的可变区;每条链的可变区包含三个高变区,也称为互补决定区(CDR)(重链(H)包含HCDR1、HCDR2和HCDR3,且轻链(L)包含LCDR1、LCDR2和LCDR3;对于定义,参见Kabat等人, Sequences of Proteins of ImmunologicalInterest, 第五版(1991), Vol. 1-3, NIH Publication 91-3242, Bethesda Md)。
本发明部分涉及具有本文所述的序列的抗CTLA4抗体。本发明的抗体可以特异性结合CTLA4。它们可以阻断CLTA4与B7的结合,特别是减轻CTLA4对机体的免疫抑制,并且非常有效地活化T淋巴细胞。
具体而言,本发明涉及本文描述为4G10的小鼠抗体,其包含SEQ ID NO:4的重链可变区(VH)和SEQ ID NO:6的轻链可变区(VL);和该抗体的人源化版本。
在一些实施方案中,4G10抗体的人源化VH序列可以包含以下VH区中的任一个:
- 4G10H1 (SEQ ID NO:8)
- 4G10H3 (SEQ ID NO:12)
- 4G10H4 (SEQ ID NO:16)
- 4G10H5 (SEQ ID NO:18)
- 4G10 H共有序列(SEQ ID NO:19)。
在一些实施方案中,4G10抗体的人源化VH序列可以包含以下CDR区(根据Kabat确定):
- HCDR1: SEQ ID NO:21,
- HCDR2: SEQ ID NO:22,
- HCDR3: SEQ ID NO:23,
在替代实施方案中,4G10抗体的人源化VH序列可以包含以下CDR区(通过VBASE2数据库分析确定):
- HCDR1: SEQ ID NO:27,
- HCDR2: SEQ ID NO:28
- HCDR3: SEQ ID NO:29。
在一些实施方案中,4G10抗体的人源化VL序列可以包含以下VL区中的任一个:
- 4G10L1 (SEQ ID NO:10)
- 4G10L3 (SEQ ID NO:14)
- 4G10 L共有序列(SEQ ID NO:20)。
在一些实施方案中,4G10抗体的人源化VL序列可以包含以下CDR区(所述CDR区根据Kabat确定):
- LCDR1: SEQ ID NO:24,
- LCDR2: SEQ ID NO:25,
- LCDR3: SEQ ID NO:26,
在替代实施方案中,4G10抗体的人源化VL序列可以包含以下CDR区(所述CDR区根据VBASE2数据库分析确定):
- LCDR1: SEQ ID NO:30,
- LCDR2: SEQ ID NO:31,
- LCDR3: SEQ ID NO:32。
任何上述人源化VH区可以与任何上述人源化VL区配对。在优选的实施方案中,本发明包括包含SEQ ID NO:19的VH区和SEQ ID NO:20的VL区的抗体。在优选的实施方案中,本发明包括包含SEQ ID NO:8的VH区和SEQ ID NO:10的VL区的抗体。在优选的实施方案中,本发明包括包含SEQ ID NO:12的VH区和SEQ ID NO:14的VL区的抗体。在优选的实施方案中,本发明包括包含SEQ ID NO:16的VH区和SEQ ID NO:14的VL区的抗体。在优选的实施方案中,本发明包括包含SEQ ID NO:18的VH区和SEQ ID NO:14的VL区的抗体。
抗体表达
本发明的抗体和抗体片段可以使用本领域技术人员已知的任何方法制备。本发明的抗体或抗体片段可以在任何宿主细胞中制备。真核和原核宿主细胞,包括哺乳动物细胞作为用于表达本文公开的抗体或片段或免疫球蛋白链的宿主,是本领域中众所周知的,且包括许多可得自美国典型培养物保藏中心(American Type Culture Collection,ATCC)的永生化细胞系。这些尤其包括中国仓鼠卵巢(CHO)细胞、NSO、SP2细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人类肝细胞癌细胞(例如Hep G2)、A549细胞、3T3细胞、HEK-293细胞和许多其他细胞系。哺乳动物宿主细胞包括人类、小鼠、大鼠、狗、猴、猪、山羊、牛、马和仓鼠细胞。特别优先的细胞系通过确定哪些细胞系具有高表达水平来选择。可使用的其他细胞系为昆虫细胞系,诸如Sf9细胞、两栖动物细胞、细菌细胞、植物细胞和真菌细胞。真菌细胞包括酵母和丝状真菌细胞,包括例如巴斯德毕赤酵母、芬兰毕赤酵母(Pichia finlandica)、喜海藻糖毕赤酵母(Pichia trehalophila)、考拉姆毕赤酵母(Pichia koclamae)、膜醭毕赤酵母(Pichia membranaefaciens)、微小毕赤酵母(Pichia minuta)(Ogataea minuta、林氏毕赤酵母(Pichia lindneri))、Pichia opuntiae、耐热毕赤酵母(Pichia thermotolerans)、Pichia salictaria、Pichia guercuum、皮杰普氏毕赤酵母(Pichia pijperi)、Pichia stiptis、甲醇毕赤酵母(Pichia methanolica)、毕赤酵母属(Pichia sp.)、酿酒酵母(Saccharomyces cerevisiae)、酵母属(Saccharomyces sp.)、多形汉逊酵母(Hansenula polymorpha)、克鲁维酵母属(Kluyveromyces sp.)、乳酸克鲁维酵母(Kluyveromyces lactis)、白色念珠菌(Candida albicans)、构巢曲霉菌(Aspergillus nidulans)、黑曲霉(Aspergillus niger)、米曲霉(Aspergillus oryzae)、里氏木霉(Trichoderma reesei)、金孢子菌(Chrysosporium lucknowense)、镰刀菌属(Fusarium sp.)、禾谷镰孢菌(Fusarium gramineum)、镰孢霉(Fusarium venenatum)、小立碗藓(Physcomitrella patens)和粗糙脉孢菌(Neurospora crassa)。毕赤酵母属,任何酵母属、多形汉逊酵母、任何克鲁维酵母属、白色念珠菌、任何曲霉菌属、里氏木菌、金孢子菌、任何镰刀菌属、解脂耶氏酵母和粗糙脉孢菌。当将编码重链或其抗原结合部分或片段、轻链和/或其抗原结合片段的重组表达载体引入哺乳动物宿主细胞中时,抗体通过将宿主细胞培养一段足以允许抗体或片段或链在宿主细胞中表达或将其分泌至宿主细胞生长的培养基中的时间来产生。
抗体纯化
抗体和其抗原结合片段和免疫球蛋白链可使用标准蛋白纯化方法来从培养基回收。此外,可使用许多已知的技术增强本发明的抗体和其抗原结合片段和免疫球蛋白链(或来自其的其他部分)从产生细胞系的表达。例如,谷氨酰胺合成酶基因表达系统(GS系统)为用于增强在某些条件下表达的常用方法。GS系统整体或部分结合欧洲专利号0 216 846、0 256055和0 323 997和欧洲专利申请号89303964.4进行讨论。因此,在本发明的一个实施方案中,哺乳动物宿主细胞(例如CHO)缺乏谷氨酰胺合成酶基因并在培养基中不存在谷氨酰胺的情况下生长,其中然而,编码免疫球蛋白链的多核苷酸包含补充宿主细胞中基因的缺乏的谷氨酰胺合成酶基因。
本发明包括用于纯化本发明的抗体或其抗原结合片段的方法,其包括将包含抗体或片段的样品引入纯化介质(例如阳离子交换介质、阴离子交换介质、疏水性交换介质、亲和力纯化介质(例如蛋白-A、蛋白-G、蛋白-A/G、蛋白-L))且从不结合介质的所述样品的流过级分收集纯化的抗体或片段;或丢弃流过级分且从介质洗脱结合抗体或片段且收集洗脱液。在本发明的一个实施方案中,介质在施加样品的柱中。在本发明的一个实施方案中,在抗体或片段在宿主细胞中重组表达之后进行纯化方法,例如其中宿主细胞首先裂解且任选地在介质上纯化前纯化裂解物以除去不溶材料。
抗体工程改造
在某些实施方案中,本发明的抗体和其抗原结合片段被工程改造以在构架和/或CDR中包括修饰,以改善其特性。此类工程改造的变化可基于分子建模。亲本(非人类)抗体序列的可变区的分子模型可被构建以理解抗体的结构特征并用于鉴定可与抗原相互作用的抗体上的潜在区域。常规CDR基于比对免疫球蛋白序列和鉴定可变区。Kabat等人,(1991)Sequences of Proteins of Immunological Interest, Kabat,等人;NationalInstitutes of Health, Bethesda, Md.;第5版;NIH公开号91-3242;Kabat (1978) Adv. Prot. Chem. 32:1-75;Kabat等人,(1977) J. Biol. Chem. 252:6609-6616。Chothia和同事小心地检查抗体的晶体结构中环的构型且提出高变环。Chothia等人,(1987) J Mol. Biol. 196:901-917或Chothia等人,(1989) Nature 342:878-883。归类为“CDR”和“高变环”的区域之间存在变化。后来的研究(Raghunathan等人,(2012) J. Mol Recog. 25, 3,103-113)分析几种抗体-抗原晶体复合物且观察到抗体中的抗原结合区不必严格地与“CDR”残基或“高变”环一致。非人类抗体的可变区的分子模型可用于引导可潜在结合抗原的区域的选择。实际上,基于模型的潜在抗原结合区不同于常规“CDR”或“高变”环。商业科学软件诸如MOE (Chemical Computing Group)可用于分子建模。人类构架可基于构架中和CDR中与非人类序列的最佳匹配来选择。对于VH中的FR4(构架4),将人类种系的VJ区与对应非人类区域相比较。在VL中的FR4(构架4)的情况下,将人类种系序列的J-κ和J-λ区与对应非人类区相比较。一旦鉴定合适的人类构架,就将CDR移植至所选人类构架中。在一些情况下,VL-VH界面中的某些残基可如非人类(亲本)序列中保留。分子模型也可用于鉴定可潜在地改变CDR构型且因此改变与抗原的结合的残基。在一些情况下,这些残基如非人类(亲本)序列中得到保留。分子模型也可用于鉴定溶剂暴露的氨基酸,其可导致不必要作用,诸如糖基化、脱酰胺和氧化。可在设计阶段早期引入可开发性过滤器以消除/最小化这些潜在问题。
构架修饰的另一类型涉及将构架区内或甚至一个或多个CDR区内的一个或多个残基突变以去除T细胞表位,由此降低抗体的潜在免疫原性。该方法也称为“去免疫”,且进一步详细描述于美国专利号7,125,689中。
在具体实施方案中,需要将含有暴露的侧链的某些氨基酸改变成另一氨基酸残基,以提供最终抗体的更大化学稳定性,以避免脱酰胺或异构化。天冬酰胺的脱酰胺可在NG、DG、NG、NS、NA、NT、QG或QS序列上进行,且导致产生异天冬氨酸残基,其将扭结引入多肽链中且降低其稳定性(异天冬氨酸作用)。异构化可在DG、DS、DA或DT序列进行。在某些实施方案中,本发明的抗体不含脱酰胺或天冬酰胺异构位点。
例如,天冬酰胺(Asn)残基可改变成Gln或Ala以降低任何Asn-Gly序列、特别CDR内形成异天冬氨酸的潜能。相似问题可在Asp-Gly序列发生。Reissner和Aswad (2003) Cell. Mol. Life Sci. 60:1281。异天冬氨酸形成可减弱或完全废除抗体与其靶抗原的结合。参见Presta (2005) J. Allergy Clin. Immunol. 116:731第734页。在一个实施方案中,天冬酰胺改变成谷氨酰胺(Gln)。也可能需要改变与天冬酰胺(Asn)或谷氨酰胺(Gln)残基相邻的氨基酸以降低脱酰胺的可能性,当小氨基酸与天冬酰胺或谷氨酰胺相邻出现时脱酰胺以更大速率发生。参见Bischoff & Kolbe (1994) J. Chromatog. 662:261。另外,CDR中任何甲硫氨酸残基(通常溶剂暴露的Met)可改变成Lys、Leu、Ala或Phe或其他氨基酸以减小甲硫氨酸硫会氧化的可能性,其可降低抗原结合亲和力且还有助于最终抗体制剂中的分子异质性。同上。另外,为了预防或最小化潜在易切断的Asn-Pro肽键,可能需要将在CDR中发现的任何Asn-Pro组合改变成Gln-Pro、Ala-Pro或Asn-Ala。随后筛选具有此类取代的抗体以确保所述取代不使抗体对CTLA4的亲和力或特异性或其他所需生物活性降低至不可接受的水平。
Fc区的抗体工程改造
本文公开的抗体(例如人源化抗体)和其抗原结合片段也可工程改造以在Fc区内包括修饰,通常改变抗体的一种或多种特性,诸如血清半衰期、补体结合、Fc受体结合和/或效应子功能(例如抗原依赖性细胞毒性)。此外,本文公开的抗体和其抗原结合片段可被化学修饰(例如一个或多个化学部分可附接至抗体)或被修饰以改变其糖基化,再次改变抗体或片段的一种或多种特性。
抗体缀合物
本发明还包括抗体缀合物,其包含本发明的抗体或抗原结合片段。本发明的抗体可以与化学部分缀合。化学部分可尤其为聚合物、放射性核素或细胞毒性因子。在具体实施方案中,化学部分是增加抗体或片段在个体体内的半衰期的聚合物。合适的聚合物包括,但不限于,亲水性聚合物,其包括,但不限于,聚乙二醇(PEG)(例如分子量为2kDa、5kDa、10kDa、12kDa、20kDa、30kDa或40kDa的PEG)、葡聚糖和单甲氧基聚乙二醇(mPEG)。Lee等人(1999)(Bioconj. Chem. 10:973-981)公开PEG缀合的单链抗体。Wen等人(2001) (Bioconj. Chem. 12:545-553)公开了用附接至放射金属螯合剂(二乙烯三胺五乙酸(DTPA))的PEG缀合抗体。
本文公开的抗体和其抗原结合片段也可与标记物缀合,所述标记物诸如99Tc、90Y、111In、32P、14C、125I、3H、131I、11C、15O、13N、18F、35S、51Cr、57To、226Ra、60Co、59Fe、57Se、152Eu、67CU、217Ci、211At、212Pb、47Sc、109Pd、234Th和40K、157Gd、55Mn、52Tr和56Fe。
本文公开的抗体和抗原结合片段也可与荧光或化学发光标记物缀合,所述标记物包括荧光团,诸如稀土螯合物、荧光素和其衍生物、若丹明和其衍生物、异硫氰酸酯、藻红蛋白、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛、荧光胺、152Eu、丹磺酰基、伞酮、荧光素、鲁米那标记物、异鲁米那标记物、芳族吖啶酯标记物、咪唑标记物、吖啶盐标记物、草酸酯标记物、水母素标记物、2,3-二氢酞嗪二酮、生物素/抗生素蛋白、旋转标记物和稳定自由基。
本发明的抗体和其抗原结合片段也可缀合至细胞毒性因子,诸如白喉毒素、绿脓假单胞菌外毒素A链、蓖麻毒素A链、相思豆毒素A链、蒴莲素A链、α-八叠球菌、油桐(Aleurites fordii)蛋白和化合物(例如脂肪酸)、香石竹毒蛋白、美洲商陆(Phytoiacca americana)蛋白PAPI、PAPII和PAP-S、苦瓜(momordica charantia)抑制剂、麻风树毒蛋白、巴豆毒素、肥皂草(saponaria officinalis)抑制剂、有丝分裂素(mitogellin)、局限曲菌素、酚霉素和伊诺霉素(enomycin)。
可采用本领域中已知的用于将本发明的抗体和其抗原结合片段缀合至各种部分的任何方法,包括由Hunter等人(1962) Nature 144:945;David等人(1974) Biochemistry13:1014;Pain等人(1981) J. Immunol. Meth. 40:219;和Nygren, J., (1982)Histochem. and Cytochem. 30:407描述的方法。用于缀合抗体和片段的方法是本领域中常规和众所周知的。
抗CTLA4抗体的治疗用途
进一步提供用于治疗需要用本文公开的分离的抗体或其抗原结合片段治疗的个体、包括人类个体的方法。在本发明的一个实施方案中,此类个体患有感染或感染性疾病。在本发明的另一个实施方案中,此类个体患有癌症。在一个实施方案中,癌症是例如骨肉瘤、横纹肌肉瘤、神经母细胞瘤、肾癌、白血病、肾移行细胞癌、膀胱癌、维尔姆氏癌(Wilm'scancer)、卵巢癌、胰腺癌、乳腺癌、前列腺癌、骨癌、肺癌(例如非小细胞肺癌)、胃癌、结肠直肠癌、子宫颈癌、滑膜肉瘤、头颈癌、鳞状细胞癌、多发性骨髓瘤、肾细胞癌、视网膜母细胞瘤、肝母细胞瘤、肝细胞癌、黑色素瘤、肾横纹肌样瘤、尤因氏肉瘤(Ewing's sarcoma)、软骨肉瘤、脑癌、胶质母细胞瘤、脑膜瘤、垂体腺瘤、前庭神经鞘瘤、原始神经外胚层瘤、成神经管细胞瘤、星形细胞瘤、间变性星形细胞瘤、少突神经胶质瘤、室管膜瘤、脉络丛乳头状瘤、真性红细胞增多症、血小板增多症、特发性骨髓纤维化、软组织肉瘤、甲状腺癌、子宫内膜癌、类癌瘤癌或肝癌、乳腺癌或胃癌。在本发明的一个实施方案中,癌症是转移性癌症,例如上述种类的转移性癌症。
在一个实施方案中,本发明提供使用本发明的抗体或其抗原结合片段治疗个体的方法,其中所述个体患有病毒感染。在一个实施方案中,所述病毒感染是被选自以下的病毒感染:人类免疫缺乏病毒(HIV)、肝炎病毒(A、B或C)、疱疹病毒(例如VZV、HSV-I、HAV-6、HSV-II和CMV、Epstein-Barr病毒)、腺病毒、流感病毒、黄病毒、艾柯病毒、鼻病毒、柯萨奇病毒、冠状病毒、呼吸道合胞病毒、腮腺炎病毒、轮状病毒、麻疹病毒、风疹病毒、细小病毒、牛痘病毒、HTLV病毒、登革热病毒、乳头状瘤病毒、软疣病毒、脊髓灰质炎病毒、狂犬病病毒、JC病毒或虫媒病毒性脑炎病毒。
在一个实施方案中,本发明提供使用本发明的抗体或其抗原结合片段治疗个体的方法,其中所述个体患有细菌感染。在一个实施方案中,细菌感染是被选自以下的细菌感染:衣原体(Chlamydia)、立克次体细菌(rickettsial bacteria)、分枝杆菌(mycobacteria)、葡萄球菌(staphylococci)、链球菌(streptococci)、肺炎球菌(pneumonococci)、脑膜炎球菌(meningococci)和淋球菌(gonococci)、克雷伯氏菌(klebsiella)、变形杆菌(proteus)、沙雷氏菌属(serratia)、假单胞菌(pseudomonas)、军团杆菌属(Legionella)、白喉棒状杆菌(Corynebacterium diphtheriae)、沙门氏菌(Salmonella)、芽孢杆菌(bacilli)、霍乱弧菌(Vibrio cholerae)、破伤风梭菌(Clostridium tetan)、肉毒梭状芽孢杆菌(Clostridium botulinum)、炭疽芽孢杆菌(Bacillus anthricis)、鼠疫耶尔森菌(Yersinia pestis)、麻风分支杆菌(Mycobacterium leprae)、弥漫型麻风分枝杆菌(Mycobacterium lepromatosis)和包柔氏螺旋体(Borriella)。
在一个实施方案中,本发明提供使用本发明的抗体或其抗原结合片段治疗个体的方法,其中所述个体患有真菌感染。在一个实施方案中,真菌感染是被选自以下的真菌感染:念珠菌属(Candida)(白色念珠菌(albicans)、克鲁斯氏念珠菌(krusei)、光滑念珠菌(glabrata)、热带念珠菌(tropicalis)等)、新型隐球菌(Cryptococcus neoformans)、曲霉菌属(Aspergillus)(烟曲霉(fumigatus)、黑曲霉(niger)等)、毛霉菌属(GenusMucorales)(白霉菌属(mucor)、犁头霉属(absidia)、根霉菌属(rhizopus))、申克氏胞丝菌(Sporothrix schenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球孢子菌(Coccidioides immitis)和荚膜组织胞浆菌(Histoplasma capsulatum)。
在一个实施方案中,本发明提供使用本发明的抗CTLA4抗体或其抗原结合片段治疗个体的方法,其中所述个体患有寄生虫感染。在一个实施方案中,寄生虫感染是被选自以下的寄生虫感染:溶组织内阿米巴(Entamoeba histolytica)、结肠小袋纤毛虫(Balantidium coli)、福氏纳格里阿米巴原虫(Naegleria fowleri)、棘阿米巴虫属(Acanthamoeba)、篮氏贾第鞭毛虫(Giardia lambia)、隐胞子虫属(Cryptosporidium)、卡氏肺孢子虫(Pneumocystis carinii)、间日疟原虫(Plasmodium vivax)、微小巴贝虫(Babesia microti)、布氏锥虫(Trypanosoma brucei)、克氏锥虫(Trypanosoma cruzi)、杜氏利什曼原虫(Leishmania donovani)、刚地弓形虫(Toxoplasma gondii)和巴西日圆线虫(Nippostrongylus brasiliensis)。
“个体”可以是哺乳动物,诸如人类、犬、猫、马、牛、小鼠、大鼠、猴(例如食蟹猴,例如食蟹猴)或兔。在本发明的优选实施方案中,所述个体为人类个体。
在具体实施方案中,本文公开的抗体或其抗原结合片段可单独或与其他另外治疗剂和/或治疗程序联合使用,用于治疗或预防需要此类治疗或预防的个体中的任何疾病诸如癌症,例如如本文中所讨论。包含此类抗体和片段与另外治疗剂联合的组合物,例如包含药学上可接受的载体的药物组合物,也是本发明的一部分。
在具体实施方案中,本文公开的抗体或其抗原结合片段可单独或与肿瘤疫苗联合使用。
在具体实施方案中,本文公开的抗体或其抗原结合片段可单独或与化学治疗剂联合使用。
在具体实施方案中,本文公开的抗体或其抗原结合片段可单独或与放射疗法联合使用。
在具体实施方案中,本文公开的抗体或其抗原结合片段可单独或与靶向疗法联合使用。靶向疗法的实例包括:激素疗法、信号转导抑制剂(例如EGFR抑制剂,诸如西妥昔单抗(Erbitux)和埃罗替尼(Tarceva));HER2抑制剂(例如曲妥珠单抗(Herceptin)和帕妥珠单抗(Perjeta));BCR-ABL抑制剂(诸如伊马替尼(Gleevec)和达沙替尼(Sprycel));ALK抑制剂(诸如克里唑替尼(Xalkori)和色瑞替尼(Zykadia));BRAF抑制剂(诸如维罗非尼(Zelboraf)和达拉菲尼(Tafinlar))、基因表达调节剂、细胞凋亡诱导剂(例如硼替佐米(Velcade)和卡非佐米(Kyprolis))、血管生成抑制剂(例如贝伐单抗(Avastin)和雷莫芦单抗(Cyramza))、附接至毒素的单克隆抗体(例如brentuximab vedotin (Adcetris)和阿多曲妥珠单抗恩他新(ado-trastuzumab emtansine)(Kadcyla))。
在具体实施方案中,本发明的抗体或其抗原结合片段可与抗癌治疗剂或免疫调节药物,诸如免疫调节受体抑制剂,例如特异性结合受体的抗体或其抗原结合片段组合使用。
因此,本发明包括包含本发明的抗体或其抗原结合片段与派姆单抗联合的组合物;以及用于治疗或预防个体中的癌症的方法,其包括向所述个体施用有效量的本发明的抗CTLA4抗体或其抗原结合片段和派姆单抗。任选地,还向所述个体施用另外的治疗剂。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与以下中的一种或多种联合:抗PD1抗体(例如派姆单抗、尼沃单抗、皮立珠单抗(pidilizumab)(CT-011))、抗PDL1抗体、抗CTLA4抗体、抗CS1抗体(例如埃罗妥珠单抗(elotuzumab))、抗KIR2DL1/2/3抗体(例如利瑞鲁单抗(lirilumab))、抗CD137抗体(例如乌鲁单抗(urelumab))、抗GITR抗体(例如TRX518)、抗PD-L1抗体(例如BMS-936559、MSB0010718C或MPDL3280A)、抗PD-L2抗体、抗ILT1抗体、抗ILT2抗体、抗ILT3抗体、抗ILT4抗体、抗ILT5抗体、抗ILT6抗体、抗ILT7抗体、抗ILT8抗体、抗CD40抗体、抗OX40抗体、抗ICOS、抗SIRPα、抗KIR2DL1抗体、抗KIR2DL2/3抗体、抗KIR2DL4抗体、抗KIR2DL5A抗体、抗KIR2DL5B抗体、抗KIR3DL1抗体、抗KIR3DL2抗体、抗KIR3DL3抗体、抗NKG2A抗体、抗NKG2C抗体、抗NKG2E抗体、抗4-1BB抗体(例如PF-05082566)、抗TSLP抗体、抗IL-10抗体、IL-10或聚乙二醇化的IL-10或此类靶标的任何小有机分子抑制剂。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗PD1抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗PDL1抗体(例如,BMS-936559、MSB0010718C或MPDL3280A)联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗TIGIT抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗CS1抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL1/2/3抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗CD137 (例如,乌鲁单抗(urelumab))抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗GITR (例如,TRX518)抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗PD-L2抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL1抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL2抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL3抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL4抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL5抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL6抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL7抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ITL8抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗CD40抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗OX40抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL1抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL2/3抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL4抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL5A抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR2DL5B抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR3DL1抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR3DL2抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗KIR3DL3抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗NKG2A抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗NKG2C抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗ICOS抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗SIRPα抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗4-1BB抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗IL-10抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗TSLP抗体联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与IL-10或PEG化IL-10联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与诸如以下的抑制剂(例如小有机分子或抗体或其抗原结合片段)中的一种或多种联合:MTOR(哺乳动物雷帕霉素靶标)抑制剂、细胞毒性剂、铂剂、EGFR抑制剂、VEGF抑制剂、微管稳定剂、紫杉烷、CD20抑制剂、CD52抑制剂、CD30抑制剂、RANK(核因子κ-B的受体活化物)抑制剂、RANKL(核因子κ-B配体的受体活化物)抑制剂、ERK抑制剂、MAP激酶抑制剂、AKT抑制剂、MEK抑制剂、PI3K抑制剂、HER1抑制剂、HER2抑制剂、HER3抑制剂、HER4抑制剂、Bcl2抑制剂、CD22抑制剂、CD79b抑制剂、ErbB2抑制剂或法呢基蛋白转移酶抑制剂。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与以下中的任何一种或多种联合:13-顺-视黄酸、(3-[5-(甲基磺酰基哌啶甲基)-吲哚基]-喹诺酮)、4-羟基他莫昔芬、5-脱氧尿苷、5'-脱氧-5-氟尿苷、5-氟尿嘧啶、6-巯基嘌呤、7-羟基星孢菌素、A-443654、醋酸阿比特龙、abraxane、ABT-578、阿考比芬、ADS-100380、ALT-110、六甲蜜胺、阿米福汀、氨鲁米特、氨柔比星、安吖啶、阿那格雷、阿那曲唑、血管生长抑制因子、AP-23573、ARQ-197、阿佐昔芬、AS-252424、AS-605240、天冬酰胺酶、AT-9263、阿曲生坦、阿西替尼、AZD1152、卡介(Bacillus Calmette-Guerin,BCG)疫苗、batabulin、BC-210、besodutox、贝伐单抗、比卡鲁胺、Bio111、BIO140、博莱霉素、BMS-214662、BMS-247550、BMS-275291、BMS-310705、硼替佐米、布舍瑞林、白消安、骨化三醇、喜树碱、卡奈替尼、卡培他滨、卡铂、卡莫司汀、CC8490、西地尼布、CG-1521、CG-781、查米多星(chlamydocin)、苯丁酸氮芥、氯毒素、西仑吉肽、西米替丁、顺铂、克拉屈滨、氯屈膦酸盐、COL-3、CP-724714、环磷酰胺、环丙孕酮、醋酸环丙氯地孕酮、阿糖胞苷(cytarabine)、阿糖胞苷(cytosinearabinoside)、达卡巴嗪、达西司特、放线菌素D、dalotuzumab、达鲁舍替、达沙替尼(dasatanib)、道诺霉素、地卡塔尼(decatanib)、鱼藤素、地尼白介素、脱氧柯福霉素、缩酚肽、二芳基丙腈、二乙基己烯雌酚、diftitox、多西他赛、多韦替尼、阿霉素、屈洛昔芬、艾特咔林(edotecarin)、钇90标记的艾多替德(yttrium-90 labeled-edotreotide)、艾多替德(edotreotide)、EKB-569、EMD121974、内皮抑素、恩杂鲁胺、enzastaurin、表柔比星、埃博霉素B、ERA-923、Erbitux、埃罗替尼、雌二醇、雌氮芥、依托泊苷、依维莫司、依西美坦、ficlatuzumab、非那雄胺、夫拉平度、氟尿苷、氟达拉宾、氟氢可的松、氟甲睾酮、氟他胺、FOLFOX方案、氟维司群、galeterone、吉非替尼、吉西他滨、吉马替康、戈舍瑞林、乙酸戈舍瑞林、棉酚、GSK461364、GSK690693、HMR-3339、己酸羟孕酮、羟基脲、IC87114、伊达比星、idoxyfene、异环磷酰胺、IM862、伊马替尼、IMC-1C11、INCB24360、INO1001、干扰素、白介素-12、伊匹单抗、伊立替康、JNJ-16241199、酮康唑、KRX-0402、拉帕替尼、拉索昔芬、来曲唑、甲酰四氢叶酸、亮丙瑞林、乙酸亮丙瑞林、左旋咪唑、脂质体包覆的紫杉醇、洛莫司汀、洛那法尼、硫蒽酮、LY292223、LY292696、LY293646、LY293684、LY294002、LY317615、马立马司他、氮芥(mechlorethamine)、甲羟孕酮乙酸酯、甲地孕酮乙酸酯、美法仑、巯基嘌呤、美司钠、甲氨蝶呤、光神霉素、丝裂霉素、米托坦、米托蒽醌、陶扎色替、MLN8054、癌立消(neovastat)、来那替尼、neuradiab、尼罗替尼、nilutimide、诺拉曲特、NVP-BEZ235、oblimersen、奥曲肽、奥法木单抗、奥戈伏单抗、orteronel、奥沙利铂、紫杉醇、帕博西尼、帕米膦酸盐、帕尼单抗、帕唑帕尼、PD0325901、PD184352、PEG-干扰素、培美曲塞、喷司他丁、哌立福新、苯丙氨酸氮芥、PI-103、pictilisib、PIK-75、哌喷昔芬、PKI-166、普卡霉素、卟吩姆(porfimer)、泼尼松、丙卡巴肼、孕酮、PX-866、R-763、雷洛昔芬、雷替曲塞、razoxin、地磷莫司、利妥昔单抗、罗米地辛、RTA744、鲁比替康、scriptaid、Sdx102、seliciclib、司美替尼、司马沙尼(semaxanib)、SF1126、西罗莫司、SN36093、索拉非尼、螺内酯、角鲨胺、SR13668、链脲菌素、SU6668、辛二酰苯胺异羟肟酸(suberoylanalide hydroxamic acid)、舒尼替尼、合成雌激素、他仑帕奈、塔利拉维(talimogene laherparepvec)、他莫昔芬、替莫唑胺、坦罗莫司、替尼泊苷、替米利芬、睾酮(testosterone)、粉防己碱(tetrandrine)、TGX-221、沙利多胺、硫鸟嘌呤、噻替派、替西单抗(ticilimumab)、替吡法尼、替沃扎尼(tivozanib)、TKI-258、TLK286、拓朴替康、柠檬酸托瑞米芬、曲贝替定、曲妥珠单抗、维甲酸、曲古抑菌素A、磷酸曲西立滨单水合物、双羟萘酸曲普瑞林、TSE-424、尿嘧啶氮芥、丙戊酸、戊柔比星、凡德他尼、瓦他拉尼(vatalanib)、VEGF捕获物、长春花碱、长春新碱、长春地辛、长春瑞滨、vitaxin、vitespan、伏立诺他(vorinostat)、VX-745、渥曼青霉素、Xr311、zanolimumab、ZK186619、ZK-304709、ZM336372、ZSTK474。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与一种或多种止吐药联合,所述止吐药包括,但不限于:卡索匹坦(GlaxoSmithKline)、奈妥吡坦(Netupitant)(MGI-Helsinn)和其他NK-1受体拮抗剂、帕洛诺司琼(由MGI Pharma作为Aloxi销售)、阿瑞匹坦(由Merck and Co.作为Emend销售;Rahway, NJ)、苯海拉明(由Pfizer作为Benadryl®销售;New York, NY)、安泰乐(由Pfizer作为Atarax®销售;New York, NY)、甲氧氯普胺(由AH Robins Co.作为Reglan®销售;Richmond, VA)、劳拉西泮(由Wyeth作为Ativan®销售;Madison, NJ)、阿普唑仑(由Pfizer作为Xanax®销售;New York, NY)、氟哌啶醇(由Ortho-McNeil作为Haldol®销售;Raritan, NJ)、氟哌利多(Inapsine®)、屈大麻酚(由Solvay Pharmaceuticals, Inc.作为Marinol®销售;Marietta,GA)、地塞米松(由Merckand Co.作为Decadron®销售;Rahway, NJ)、甲基泼尼龙(由Pfizer作为Medrol®销售;NewYork, NY);丙氯拉嗪(由Glaxosmithkline作为Compazine®销售;Research TrianglePark, NC)、格拉司琼(由Hoffmann-La Roche Inc.作为Kytril®销售;Nutley, NJ)、昂丹司琼(由Glaxosmithkline作为Zofran®销售;Research Triangle Park, NC)、多拉司琼(由Sanofi-Aventis作为Anzemet®销售;New York, NY)、托烷司琼(由Novartis作为Navoban®销售;East Hanover, NJ)。
癌症治疗的其他副作用包括红细胞和白细胞缺乏。因此,在本发明的一个实施方案中,抗体或其抗原结合片段与治疗或预防此类缺乏的药剂(诸如例如非格司亭(filgrastim)、PEG-非格司亭、红细胞生成素、阿法依泊汀(epoetin alfa)或阿法达贝泊汀(darbepoetin alfa))联合。
在本发明的一个实施方案中,本发明的抗体或其抗原结合片段与抗癌放射疗法联合施用。例如,在本发明的一个实施方案中,放射疗法为外部束疗法(EBT):用于递送一束高能X射线至肿瘤位置的方法。所述束在患者外面产生(例如通过线性加速器)且靶向在肿瘤部位。这些X射线可破坏癌细胞且小心的治疗计划允许绕过周围正常组织。不将放射性源置于患者体内。在本发明的一个实施方案中,放射疗法是质子束疗法:以质子代替X-射线轰击患病组织的一种类型的适形疗法。在本发明的一个实施方案中,放射疗法是适形外部束放射疗法:使用先进技术将放射疗法针对个体机体结构调整的程序。在本发明的一个实施方案中,放射疗法为短程疗法:放射性物质暂时置于体内,通常用以将超剂量或增强剂量的放射给予区域。
在本发明的一个实施方案中,与抗体或其抗原结合片段联合施用的手术程序是手术肿瘤切除术。
术语“联合”指示在本发明的方法中施用的组分可配制成单一组合物以同时递送,或分开配制成两种或更多种组合物(例如试剂盒)。各组分可在不同于施用其他组分的时间向个体施用;例如,每次施用可经给定时间段以几种时间间隔非同时给予(例如分开或依次)。此外,分开的组分可通过相同或不同途径向个体施用。
药物组合物和施用
为了制备本发明的抗体和抗原结合片段的药物或无菌组合物,将抗体或其抗原结合片段与药学上可接受的载体或赋形剂混合。参见例如 Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company,Easton, PA (1984)。
治疗和诊断剂的制剂可通过以例如冻干粉末、浆液、水性溶液或悬浮液的形式与可接受的载体、赋形剂或稳定剂混合来制备(参见例如Hardman等人(2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York,NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy,Lippincott, Williams, and Wilkins, New York, NY; Avis, 等人(编辑) (1993)Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY;Lieberman, 等人(编辑) (1990) Pharmaceutical Dosage Forms: Tablets, MarcelDekker, NY; Lieberman, 等人(编辑) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner和Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY)。
单独或与另一治疗剂组合施用的本发明抗体的毒性和治疗功效可通过标准药物程序在细胞培养物或实验动物中测定,例如用于测定LD50(对群体的50%致死的剂量)和ED50(群体的50%中治疗有效的剂量)。毒性和治疗作用之间的剂量比率为治疗指数(LD50/ED50)。从这些细胞培养物测定和动物研究获得的数据可用于配制用于人类的剂量范围。此类化合物的剂量优选在循环浓度的范围内,所述循环浓度包括活性很小或无毒性的ED50。剂量可根据所采用的剂型和施用途径而在该范围内变化。
在一个进一步实施方案中,根据Physicians' Desk Reference 2003 (ThomsonHealthcare;第57版(2002年11月1日)),另外的治疗剂与本发明的抗体或其抗原结合片段联合向个体施用。
施用模式可变化。施用途径包括经口、直肠、经粘膜、经肠、肠胃外;肌肉内、皮下、皮内、髓内、鞘内、直接心室内、静脉内、腹膜内、鼻内、眼内、吸入、吹入、局部、皮肤、经皮或动脉内。
在具体实施方案中,本发明的抗体或其抗原结合片段可通过侵袭性途径、诸如通过注射来施用。在本发明的进一步实施方案中,抗体或其抗原结合片段或其药物组合物静脉内、皮下、肌肉内、动脉内、瘤内或通过吸入、气溶胶递送来施用。通过非侵袭性途径(例如经口;例如在丸剂、胶囊或锭剂中)施用也在本发明的范围内。
本发明提供容器(例如塑料或玻璃小瓶,例如具有盖或色谱柱、中空孔针或注射器圆筒),其包含任一本发明的抗体或抗原结合片段或其药物组合物。本发明还提供注射装置,其包含任一本发明的抗体或抗原结合片段或其药物组合物。注射装置是经由肠胃外途径,例如肌肉内、皮下或静脉内,将物质引入患者体内的装置。例如,注射装置可以是注射器(例如预填充有药物组合物,诸如自动注射器),其例如包括用于容纳待注射的流体(例如抗体或片段或其药物组合物)的针筒或圆筒、用于刺穿皮肤和/或血管以注射流体的针;以及用于推动流体从针筒出来且穿过针孔的栓塞。在本发明的一个实施方案中,包含本发明的抗体或其抗原结合片段或其药物组合物的注射装置为静脉内(IV)注射装置。此类装置包括套管或套管针/针中的抗体或片段或其药物组合物,所述套管或套管针/针可附接至管,所述管可附接至用于容纳通过套管或套管针/针引入患者体内的流体(例如盐水;或包含NaCl、乳酸钠、KCl、CaCl2且任选地包括葡萄糖的乳酸化林格氏溶液)的袋子或储器。在本发明的一个实施方案中,一旦将套管针和套管插入个体静脉中且从插入套管移除套管针,抗体或片段或其药物组合物可引入装置中。IV装置可例如插入周围静脉(例如手或臂中);上腔静脉或下腔静脉,或心脏右心房(例如中央IV)内;或锁骨下、颈内静脉或股静脉,且例如前进至心脏,直至其达到上腔静脉或右心房(例如中央静脉)。在本发明的一个实施方案中,注射装置为自动注射器;喷射注射器或外部输注泵。喷射喷射器使用液体的高压狭窄喷射,其穿透表皮层以将抗体或片段或其药物组合物引入患者体内。外部输注泵为将抗体或片段或其药物组合物以受控量递送至患者体内的医学装置。外部输注泵可以是电动或机械动力的。不同泵以不同方式操作,例如注射泵保持流体在注射器储器中,且可移动活塞控制流体递送,弹性泵保持流体在可拉伸的气球储器中,且来自气球的弹性壁的压力驱动流体递送。在蠕动泵中,一组滚筒在柔性导管长度上向下挤压,推动流体向前。在多通道泵中,流体可从多个储器以多个速率递送。
本文公开的药物组合物也可用无针皮下注射装置施用;诸如美国专利号6,620,135;6,096,002;5,399,163;5,383,851;5,312,335;5,064,413;4,941,880;4,790,824或4,596,556中公开的装置。此类包含药物组合物的无针装置也是本发明的一部分。本文公开的药物组合物也可通过输注施用。众所周知用于施用药物组合物的植入物和模块的实例包括以下中公开的那些:美国专利号4,487,603,其公开以受控速率分配药物的可植入微输注泵;美国专利号4,447,233,其公开以精确输注速率递送药物的药物输注泵;美国专利号4,447,224,其公开用于连续药物递送的可变流量可植入输注设备;美国专利号4,439,196,其公开具有多腔室隔室的渗透药物递送系统。许多其他此类植入物、递送系统和模块是本领域技术人员众所周知的,且包含本发明的药物组合物的那些植入物、递送系统和模块在本发明的范围内。
或者,可以局部而非全身性方式,例如经由直接注射抗体或片段至肿瘤来施用本发明的抗体或抗原结合片段。此外,可在靶向药物递送系统中,例如在用靶向例如肿瘤(例如通过免疫病理学表征)的组织特异性抗体包被的脂质体中施用所述抗体或片段。将脂质体靶向至患病组织且通过患病组织选择性吸收。此类方法和脂质体是本发明的一部分。
施用方案取决于几个因素,包括治疗抗体或抗原结合片段的血清或组织转换率、症状水平、治疗性抗体的免疫原性和生物基质中靶细胞的可接近性。优选地,施用方案递送足够治疗抗体或片段以实现目标疾病状况的改善,同时最小化不希望的副作用。因此,递送的生物制剂的量部分地取决于特定治疗抗体和所治疗的病况的严重程度。可获得关于选择治疗抗体或片段的适当剂量的指导(参见例如Wawrzynczak (1996) Antibody Therapy,Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (编辑) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (编辑)(1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases,Marcel Dekker, New York, NY; Baert, 等人 (2003) New Engl. J. Med. 348:601-608; Milgrom 等人(1999) New Engl. J. Med. 341:1966-1973; Slamon等人 (2001)New Engl. J. Med. 344:783-792; Beniaminovitz 等人(2000) New Engl. J. Med.342:613-619; Ghosh等人 (2003) New Engl. J. Med. 348:24-32; Lipsky等人(2000)New Engl. J. Med. 343:1594-1602)。
适当剂量的确定通过临床医师,例如使用本领域中已知或怀疑影响治疗的参数或因素进行。通常,剂量以略小于最佳剂量的量开始,且其随后以较小增量增加,直至相对于任何负面的副作用实现所要或最佳作用。重要的诊断量度包括例如炎症的症状或所产生炎性细胞因子的水平的量度。通常,期望将使用的生物制剂来源于与靶向治疗的动物相同的物种,由此最小化对试剂的任何免疫反应。在人类个体的情况下,例如人源化和完全人类抗体可以是期望的。
本文公开的抗体或其抗原结合片段可通过连续输注或通过施用的剂量,例如每日、每周1-7次、每周、每两周、每个月、每两个月、每季、每半年、每年等提供。可例如静脉内、皮下、局部、经口、经鼻、经直肠、肌肉内、颅内、脊椎内或通过吸入提供剂量。总每周剂量通常为至少0.05μg/kg体重,更通常至少0.2μg/kg、0.5μg/kg、1μg/kg、10μg/kg、100μg/kg、0.25mg/kg、1.0mg/kg、2.0mg/kg、5.0mg/ml、10mg/kg、25mg/kg、50mg/kg或更多(参见例如Yang等人(2003) New Engl. J. Med. 349:427-434;Herold, 等人(2002) New Engl. J. Med. 346:1692-1698; Liu, 等人(1999) J.Neurol. Neurosurg. Psych. 67:451-456;Portielji, 等人 (20003) Cancer Immunol. Immunother. 52:151-144)。也可提供剂量以实现个体血清中抗CTLA4抗体的预定靶浓度,诸如0.1、0.3、1、3、10、30、100、300μg/ml或更多。在其他实施方案中,本发明的抗CTLA4抗体例如皮下或静脉内,每周、每两周、“每4周”、每个月、每两个月或每季以10、20、50、80、100、200、500、1000或2500 mg/个体施用。
如本文所用,术语“有效量”是指本发明的抗体或其抗原结合片段当单独或与其他治疗剂组合施用至细胞、组织或个体时有效引起疾病的一种或多种症状、例如癌症或癌症进展的可测量的改善的量。有效剂量进一步是指抗体或片段足以导致症状的至少部分改善、例如肿瘤缩小或消除、肿瘤生长的缺乏、增加存活时间的量。当应用于单独施用的个别活性成分时,有效剂量是指单独的成分的有效剂量。当应用于组合时,有效剂量是指无论组合连续还是同时施用,导致治疗效应的活性成分的组合量。有效量的治疗剂将导致诊断量度或参数改善至少10%;通常至少20%;优选至少约30%;更优选至少40%且最优选至少50%。在主观量度用于评价疾病严重程度的情况下,有效量也可导致主观量度的改善。
试剂盒
进一步提供包含一种或多种组分的试剂盒,所述一种或多种组分包括,但不限于,如本文中所讨论的抗体或抗原结合片段与一种或多种包括但不限于如本文中所讨论的药学上可接受的载体和/或治疗剂的其他组分联合。抗体或片段和/或治疗剂可配制为纯组合物或与药学上可接受的载体组合于药物组合物中。
在一个实施方案中,所述试剂盒包括一个容器中(例如无菌玻璃或塑料小瓶中)的本发明的抗体或其抗原结合片段或其药物组合物和另一容器中(例如无菌玻璃或塑料小瓶中)的其药物组合物和/或治疗剂。
在另一个实施方案中,所述试剂盒包含本发明的组合,其在单一常用容器中包括本发明的抗体或其抗原结合片段连同药学上可接受的载体,任选地与一种或多种治疗剂组合,任选地一起配制于药物组合物中。
如果试剂盒包括用于向个体肠胃外施用的药物组合物,则所述试剂盒可包括用于进行此类施用的装置。例如,所述试剂盒可包括如上文所讨论的一种或多种皮下针或其他注射装置。
所述试剂盒可包括包装插页,其包括关于试剂盒中的药物组合物和剂型的信息。通常,此类信息帮助患者和医师有效且安全地使用封装的药物组合物和剂型。例如,以下关于本发明的组合的信息可供应于该插页中:药代动力学、药效动力学、临床研究、功效参数、适应症和用法、禁忌症、警告信息、注意事项、不良反应、过剂量、适当剂量和施用、如何供应、适当储存条件、参考文献、制造商/经销商信息和专利信息。
检测试剂盒和治疗试剂盒
还提供试剂盒,其包含包装在容器诸如小瓶或瓶中的抗体(例如人源化抗体)或其抗原结合片段,且进一步包含附接至容器或与容器一起包装的标签,所述标签描述容器的内含物且提供适应症和/或关于使用容器内含物治疗如本文所述的一种或多种疾病状态的说明书。
在一个方面,试剂盒用于治疗癌症且包含抗CTLA4抗体(例如人源化抗体)或其抗原结合片段和另一治疗剂或疫苗。试剂盒可任选地进一步包括用于肠胃外,例如静脉内施用的注射器。在另一个方面,试剂盒包含抗CTLA4抗体(例如人源化抗体)或其抗原结合片段和描述抗体或片段与疫苗或其他治疗剂的使用的附接至容器或与容器一起包装的标签。在又一个方面,试剂盒包含疫苗或其他治疗剂和描述疫苗或其他治疗剂与抗CTLA4抗体或片段的使用的附接至容器或与容器一起包装的标签。在某些实施方案中,抗CTLA4抗体和疫苗或其他治疗剂在分开小瓶中或一起组合在相同药物组合物中。
如上文在组合疗法章节中所讨论,两种治疗剂的同时施用不要求药剂同时或通过相同途径施用,只要药剂发挥其治疗作用的时间段存在重叠。涵盖同时或依次施用,如在不同日或周施用。
也可制备包含本文公开的抗体、肽、抗原结合片段或多核苷酸中的至少一种和关于使用组合物作为检测试剂或治疗剂的说明书的本文公开的治疗和检测试剂盒。用于此类试剂盒中的容器通常可包含至少一个小瓶、试管、烧瓶、瓶、注射器或其他适合容器,检测和/或治疗组合物中的一种或多种可置于其中,且优选适当等分。在还提供第二治疗剂的情况下,试剂盒也可含有第二不同容器,其中可放置该第二检测和/或治疗组合物。或者,多种化合物可制备成单一药物组合物,且可包装在单一容器装置诸如小瓶、烧瓶、注射器、瓶或其他适合单一容器中。本文公开的试剂盒通常还将包括用于严密地容纳小瓶用于商业销售的装置,诸如例如其中保持期望小瓶的注塑或吹塑塑料容器。在放射性标记物、发色、荧光生成或其他类型的可检测标记物或检测装置包括在试剂盒内的情况下,标记试剂可提供于与检测或治疗组合物本身相同的容器中,或者可以其他方式置于其中可放置且适当等分该第二组合物的第二不同容器装置中。或者,检测试剂和标记物可制备于单一容器装置中,并且在大多数情况下,试剂盒也通常包括用于严密地容纳小瓶用于商业销售和/或便于包装和递送的装置。
还提供用于进行本文所述的检测或监测方法的装置或设备。此类设备可包括其中可输入样品的腔室或管、任选包括阀或泵以引导样品流过装置的流体处理系统、任选将血浆或血清与血液分开的过滤器、用于添加捕获试剂或检测试剂的混合腔室和任选检测结合捕获试剂免疫复合物的可检测标记物的量的检测装置。样品流可以是被动的(例如通过毛细管、流体静力学或一旦施加样品就不需要进一步操纵装置的其他力)或主动的(例如通过施加经由机械泵、电渗泵、离心力或增加气压所产生的力)或通过主动力和被动力的组合。
在进一步实施方案中,还提供处理器、计算机可读存储器和存储在计算机可读存储器上且经调整以在处理器上执行以进行本文所述的任一方法的例行程序。合适计算系统、环境和/或配置的实例包括个人计算机、服务器计算机、手持式或膝上型装置、多处理器系统、基于微处理器的系统、机顶盒、可编程的消费性电子产品、网络PC、小型计算机、大型计算机、包括以上系统或装置中任一种的分布式计算环境或本领域中已知的任何其他系统。
生物材料的保藏
杂交瘤细胞系LT002 (CTLA4-4G10)在2015年6月16日以保藏号CCTCC NO:C201587保藏于中国典型培养物保藏中心(CCTCC;地址:武汉大学,武汉,中国,邮编:430072)。
具体实施方案
下面将参考实施例详细描述本发明的实施方案。本领域技术人员将理解,以下实施例应当仅说明本发明。它们无论如何不应被解释为限制本发明的范围。未描述具体技术或条件的实施例使用本领域的文献(例如,由J. Sambrook等人撰写,由Peitang HUANG等人翻译,Molecular Cloning:A Laboratory Manual, 第三版, Science Press)中公开的技术或条件或遵循与产品一起提供的说明书进行。未指明供应商的试剂和仪器是可商购的常规产品。
在以下实施例中,使用的T细胞获得自Akeso Biopharma Inc., Zhongshan,且BALB/C小鼠购自Guangdong Medical Laboratory Animal Center。
实施例1:CTLA4-mFc融合蛋白的制备
1. CTLA4-mFc基因的合成
根据设计,CTLA4-mFc (SEQ ID NO:1)通过将CTLA4基因(细胞毒性T淋巴细胞抗原4,NCBI Genbank ID:NP_005205.2)的细胞外片段,CTLA4ECD与小鼠IgG的Fc片段mFc (Igγ-2A链C区:登录号:P01863, 99-330)融合而获得。为了增加293f细胞表达系统中目标基因的表达效率,编码CTLA4-mFc蛋白序列的核酸序列在Genscript Co.进行优化,其主要考虑因素诸如密码子偏好、GC含量、mRNA的二级结构和重复序列。对编码CTLA4-mFc融合蛋白的优化基因进行测序,且融合蛋白在Genscript Co.生产。
2. pUC57simple-CTLA4-mFc质粒的构建
将CTLA4-mFc融合基因(SEQ ID NO:2)在Genscript Co.经由内切核酸酶Xba I和BamHI的限制性位点克隆至pUC57simple表达载体(由Genscript Co.提供)中,产生pUC57simple-CTLA4-mFc质粒。
3. pcDNA3.1-CTLA4-mFc重组质粒的构建和提取
pUC57simple-CTLA4-mFc质粒用内切核酸酶Xba I和BamH I消化。CTLA4-mFc融合基因片段经由电泳回收,并经由内切核酸酶Xba I和BamH I的限制性位点连接至pcDNA3.1表达载体(购自Invitrogen Co.)中。所得pcDNA3.1-CTLA4-mFc质粒用于转染大肠杆菌的DH5a菌株的感受态细胞(购自TIANGEN Co.)。转染和培养遵循说明书进行。筛选出pcDNA3.1-CTLA4-mFc阳性的大肠杆菌菌落,并遵循常规方法繁殖。然后,遵循与试剂盒一起提供的说明书,使用试剂盒(购自Tiangen Biotech (Beijing) Co. LTD, 目录号DP103-03)提取pcDNA3.1-CTLA4-mFc重组质粒。
293F的细胞(购自Invitrogen Co.)用pcDNA3.1-CTLA4-mFc重组质粒使用lipofectamin转染试剂盒(购自Invitrogen Co.)转染,并在培养箱中在37℃、5% CO2下培养。用pcDNA3.1-CTLA4-mF重组质粒转染293F细胞后7天,通过高速离心、通过微孔过滤膜的真空过滤和HiTrap蛋白A HP柱色谱从培养液纯化CTLA4-mFc融合蛋白。
纯化之后,取样品,添加至还原上样缓冲液中用于蛋白电泳,并通过SDS-PAGE电泳检测。如图1中所示,目标蛋白显示为约45kD的条带。
CTLA4-mFc融合蛋白的氨基酸序列(364 aa)为:
其中CTLA4 ECD部分用波浪线加下划线,且mFc部分用实线加下划线。
编码CTLA4-mFc融合蛋白的核苷酸序列(1092 bp)为:
其中CTLA4 ECD部分用波浪线加下划线,且mFc部分用实线加下划线。
实施例2:抗CTLA4抗体4G10的生成
1. 杂交瘤细胞系LT002的生成
使用实施例1中制备的CTLA4-mFc融合蛋白作为免疫原,通过遵循建立的方法(例如,Stewart, S.J., “Monoclonal Antibody Production”, Basic Methods in antibodyProduction and Characterization, 编辑G.C. Howard和D.R. Bethell, Boca Raton:CRC Press, 2000)将来自免疫的BALB/C小鼠(购自Guangdong Medical LaboratoryAnimal Center)的脾细胞与小鼠骨髓瘤细胞融合来获得杂交瘤细胞。
CTLA4-mFc融合蛋白用TEV蛋白酶切割,且CTLA4蛋白通过在柱上纯化来获得。将CTLA4蛋白用作抗原以包被ELISA板,且分泌特异性结合CTLA4的新型抗体的杂交瘤细胞通过一级间接ELISA筛选来获得。接下来,通过从在一级间接ELISA筛选中获得的杂交瘤细胞二级竞争性ELISA筛选来获得分泌与配体B7-1 (CD80, NCBI基因ID:941)或B7-2 (CD86,NCBI基因ID:942)竞争结合CTLA4的单克隆抗体的杂交瘤细胞。然后,经由有限稀释获得稳定的杂交瘤细胞系。将杂交瘤细胞系命名为杂交瘤细胞系LT002 (CTLA4-4G10),并将杂交瘤细胞系分泌的单克隆抗体命名为4G10。
杂交瘤细胞系LT002 (CTLA4-4G10)在2015年6月16日以保藏号CCTCC NO:C201587保藏于中国典型培养物保藏中心(CCTCC;地址:武汉大学,武汉,中国,邮编:430072)。
2. 抗CTLA4抗体4G10的制备
将上面获得的LT002细胞系在补充有10%胎牛血清与低IgG和1%青霉素-链霉素的IMDM培养基中在37℃、5% CO2下在细胞培养箱中培养。7天后,收集细胞培养物的上清液以纯化抗体4G10(对于纯化方法,参见实施例1)。
实施例3:抗CTLA4抗体4G10的序列分析和重组抗体4G10(Re)的生成
1. 4G10抗体的序列分析
遵循培养细胞/细菌总RNA提取试剂盒(Tiangen,目录号DP430)的说明书,从实施例2中培养的LT002细胞系中提取mRNA。遵循RT-PCR试剂盒的Invitrogen SuperScript® III第一链合成系统的说明书,合成cDNA并通过PCR扩增。遵循pEASY-T1克隆试剂盒(TransGen,目录号CT101)的说明书,立即对PCR扩增产物进行TA克隆。
立即对TA克隆的产物进行测序,且表5中提供了以下的测序结果:
编码重链可变区的核酸序列(372 bp):(SEQ ID NO:3)和编码的氨基酸序列(124 aa):(SEQ ID NO:4)。
编码轻链可变区的核酸序列(378 bp):(SEQ ID NO:5)和编码的氨基酸序列(126aa):(SEQ ID NO:6)。
2. 重组抗体4G10(Re)的制备
经由内切核酸酶XbaI和BamHI的限制性位点,将4G10的重链(SEQ ID NO:3和恒定区Igγ-1链C区的序列,登录号:P01857)的cDNA序列和轻链(SEQ ID NO:5和恒定区Igκ链C区,登录号:P01834)的cDNA序列分别克隆至pUC57simple载体(由Genscript Co.提供)中,分别产生质粒pUC57simple-4G10H和pUC57simple-4G10L。
质粒pUC57simple-4G10H和pUC57simple-4G10L分别用内切核酸酶HindIII和EcoRI消化。编码重链和轻链的片段经由电泳回收,并分别亚克隆至pcDNA3.1载体中。提取重组质粒并共转染至293F的细胞中。细胞培养7天之后,通过高速离心、通过微孔过滤膜的真空过滤和HiTrap蛋白A HP柱色谱从培养液纯化重组抗体4G10(Re)。
实施例4:抗CTLA4人源化抗体4G10H1L1和4G10H3L3、4G10H4L3和4G10H5L3的设计
和生成
1. 抗CTLA4人源化抗体4G10H1L1、4G10H3L3、4G10H4L3和4G10H5L3的轻链和重链序列的设计
基于CTLA4蛋白的三维晶体结构(Nat. Struct. Biol. (1997) 4, p.527)和实施例2中获得的4G10抗体的序列,抗体的结构在计算机上建模。基于该模型设计突变,产生抗体4G10H1L1、4G10H3L3、4G10H4L3和4G10H5L3的可变区序列。抗体的恒定区序列来自NCBI数据库。重链恒定区是Igγ-1链C区,登录号:P01857,且轻链恒定区是Igκ链C区,登录号:P01834。
下面提供设计的可变区序列。
(1)人源化单克隆抗体4G10H1L1的重链和轻链序列
编码重链可变区的核酸序列(345 bp):(SEQ ID NO:7)和编码的氨基酸序列(115 aa):(SEQ ID NO:8)。
编码轻链可变区的核酸序列(327 bp):(SEQ ID NO:9)和编码的氨基酸序列(109aa):(SEQ ID NO:10)。
(2)人源化单克隆抗体4G10H3L3的重链和轻链序列
编码重链可变区的核酸序列(345 bp):(SEQ ID NO:11)和编码的氨基酸序列(115aa):(SEQ ID NO:12)。
编码轻链可变区的核酸序列(327 bp):(SEQ ID NO:13)和编码的氨基酸序列(109aa):(SEQ ID NO:14)。
(3)人源化单克隆抗体4G10H4L3的重链和轻链序列
编码重链可变区的核酸序列(345 bp):(SEQ ID NO:15)和编码的氨基酸序列(115aa):(SEQ ID NO:16)。
编码轻链可变区的核酸序列(327 bp):(SEQ ID NO:13)和编码的氨基酸序列(109aa):(SEQ ID NO:14)。
(4)人源化单克隆抗体4G10H5L3的重链和轻链序列
编码重链可变区的核酸序列:(SEQ ID NO:17)和编码的氨基酸序列:(SEQ ID NO:18)。
编码轻链可变区的核酸序列(327 bp):(SEQ ID NO:13)和编码的氨基酸序列(109aa):(SEQ ID NO:14)。
2. 人源化抗体4G10H1L1、4G10H3L3、4G10H4L3和4G10H5L3的制备
遵循上文实施例2中对于4G10(Re)的制备所述的方法制备人源化抗体。分别地,将4G10H1L1的重链(SEQ ID NO:7和恒定区Ig γ-1链C区,登录号:P01857)的cDNA序列和轻链(SEQ ID NO:9和恒定区Igκ链C区,登录号:P01834)的cDNA序列、4G10H3L3的重链(SEQ IDNO:11和恒定区Ig γ-1链C区,登录号:P01857)的cDNA序列和轻链(SEQ ID NO:13和恒定区Igκ链C区,登录号:P01834)的cDNA序列和4G10H4L3的重链(SEQ ID NO:15和恒定区Ig γ-1链C区,登录号:P01857)的cDNA序列和轻链(SEQ ID NO:13和恒定区Igκ链C区,登录号:P01834)的cDNA序列克隆至pUC57simple载体(由Genscript Co.提供)中,并将4G10H5L3的重链(SEQ ID NO:17和恒定区Ig γ-1链C区,登录号:P01857)的cDNA序列和轻链(SEQ IDNO:13和恒定区Igκ链C区,登录号:P01834)的cDNA序列克隆至pUC57simple载体(由Genscript Co.提供)中,产生质粒pUC57simple-4G10H1,pUC57simple-4G10L1;pUC57simple-4G10H3和pUC57simple-4G10L3;和pUC57simple-4G10H4和pUC57simple-4G10L3以及pUC57simple-4G10H5和pUC57simple-4G10L3。然后将质粒分别亚克隆至pcDNA3.1载体中。用重组质粒转染293F的细胞之后,收集培养液,以纯化人源化抗体4G10H1L1、4G10H3L3、4G10H4L3和4G10H5L3。
实施例5:抗体的动态参数的测定
1. 抗体4G10及其人源化抗体4G10H1L1、4G10H3L3和4G10H4L3与抗原CTLA4结合的动态参数的测定
使用ForteBio分子相互作用分析仪(Octet)测定抗原 - 抗体结合的动态参数。实施例1中制备的CTLA4-mFc融合蛋白使用TEV蛋白酶切割,且CTLA4抗原通过在柱上纯化来获得。将4G10抗体通过氨基偶联固定在AR2G传感器的表面上,并用乙醇胺封闭。在PBST中平衡之后,添加CTLA4抗原用于结合。将CTLA4在PBST中连续2倍稀释,并获得以下浓度:268.1、134.1、67、33.5、16.8、8.38、4.19、0 nM。在PBST中发生解离。通过与由4G10使用的方法类似的方法检测人源化抗体4G10H1L1、4G10H3L3和4G10H4L3,且抗原浓度为180、90、45、22.5、11.25、5.625、2.813和0 nM。
测定抗体4G10及其人源化抗体4G10H1L1、4G10H3L3和4G10H4L3与抗原结合的动态参数的结果在下表1中提供,并且测定动态特征参数的结果分别显示于图2、图3和图4中。
表 1:抗原 - 抗体结合的动态参数
KD,亲和力常数;kon,抗原 - 抗体缔合速率;kdis,抗原 - 抗体解离速率;KD=kdis/kon。对照抗体10D1是抗CTLA4抗体(SEQ ID NO:35和SEQ ID NO:36)。
结果表明抗体4G10及其人源化抗体4G10H1L1和4G10H3L3对抗原具有良好的亲和力,其中抗体4G10对所述抗原具有比4G10H1L1和4G10H3L3更强的亲和力。
实施例6:通过ELISA测定抗体与抗原结合的活性
通过间接ELISA分别测定人源化抗体4G10H1L1和4G10H3L3与CTLA4结合的活性。添加抗原之后,将ELISA板在4℃下孵育过夜。在用1%BSA在37℃下封闭2小时之后,添加所述抗体,并将板在37℃下孵育30分钟。添加HRP标记的山羊抗人IgG (H+L)二抗(Jackson, 109-035-088),并添加TMB (Neogen, 308177)用于显色5分钟。在ELISA板读数器上测定450 nm波长处的吸光度。
结果显示于图5中。如图中所示,人源化抗体4G10H1L1和4G10H3L3均可以有效地结合CTLA4蛋白,并且它们的结合效率是剂量依赖性的。表2中提供了每种剂量的荧光强度。通过在结合的抗体的荧光定量分析中的曲线模拟来获得抗体4G10H1L1和4G10H3L3的结合效率EC50,其分别为0.048和0.067nM。
表2:
测定4G10H1L1和4G10H3L3与CTLA4的结合的间接ELISA
。
1.2. 通过竞争ELISA测定人源化抗体4G10H1L1和4G10H3L3与B7竞争结合CTLA4抗原的活性
根据实施例1中描述的方法制备B7/1-hFc (人B7/1 Genbank ID NP_005182.1)。将ELISA板用B7/1-hFc在4℃下包被过夜。在用1% BSA封闭2小时之后,添加所述抗体和CTLA4-mFc抗原的混合物(对于稀释物的浓度,参见表3)。在37℃下孵育30分钟之后,添加酶标记的二抗用于孵育1小时。然后,添加底物用于在37℃下孵育30分钟。在ELISA板读数器上测定450 nm处的吸光度(参见表3)。
测定所述抗体与B7-1竞争结合CTLA4抗原的结果显示于图6中。如图中所示,抗体4G10H1L1和4G10H3L3可以有效地与B7-1竞争结合CTLA4蛋白,并且它们的结合效率是剂量依赖性的。表3中提供了每种剂量的荧光强度。通过在结合的抗体4G10H1L1和4G10H3L3的荧光定量分析中的曲线模拟计算结合效率EC50,其分别为1.297 nM和1.229 nM。
表 3:测定4G10H1L1和4G10H3L3与B7竞争结合人CTLA4的效率的竞争ELISA
。
实施例7:测定所述抗体与细胞表面的抗原结合的活性的流式细胞术
首先,生成表达CTLA4的293T宿主细胞,并分别用本发明中制备的人源化抗体标记。然后,通过流式细胞术验证抗体特异性结合细胞表面上具有天然构象的抗原的能力。
1. 表达CTLA4的293T宿主细胞的生成
对于CTLA4,用质粒pLenti6.3-CTLA4转染293T的细胞(pLenti6.3购自InvitrogenCo.)。在筛选之后,获得稳定表达CTLA4的克隆细胞群(293T-CTLA4)。
2. 抗体与细胞表面上的抗原的结合的测定
遵循常规方法用胰蛋白酶消化表达如上生成的抗原的宿主细胞,并将2 × 105个细胞添加至每个收集管中。将抗体在含有1%BSA的PBS中连续稀释。在冰上与表达相应抗原的293T细胞孵育2小时之后,将100 μL FITC标记的山羊抗人IgG (1:500)添加至每个管中,并将管在冰上孵育1小时。在用PBS洗涤3次之后,添加300 μL PBS以重悬浮细胞,并在流式细胞仪上使用FITC通道检测荧光信号。
2.1测定所述抗体与细胞表面上的抗原结合的结果
人源化抗体4G10H1L1和4G10H3L3与293T-CTLA4细胞结合的结果分别显示于图7和图8中。如图中所示,4G10H1L1和4G10H3L3抗体可以有效地结合293T-CTLA4宿主细胞表面上的CTLA4靶蛋白,并且它们的结合效率是剂量依赖性的。表4中提供了每种剂量的荧光强度。通过在结合的抗体4G10H1L1和4G10H3L3的荧光定量分析中的曲线模拟来获得4G10H1L1和4G10H3L3抗体的结合效率EC50,其分别为7.58 nM和5.4 nM。
表 4:测定4G10H1L1和4G10H3L3与CTLA4宿主细胞293T-CTLA4表面上的抗原的结合的荧光强度分析
。
2. 所述抗体结合T细胞表面上的CTLA4的活性
使用Ficoll-Paque Plus (GE Healthcare, 批号:171440-02)分离PBMC的细胞,并从PBMC分离CD4+细胞。在用PHA (50μl/ml)刺激3天之后,将细胞用PBS洗涤一次。然后,以不同浓度添加抗体,其中对照抗体10D1是人抗CTLA4抗体。在冰上孵育1.5小时之后,将细胞用PBS洗涤一次。然后,添加FITC标记的抗人二抗IgG (Jackson Immunoresearch, 批号102155)。在冰上在黑暗中孵育1小时之后,将细胞用PBS洗涤一次并在流式细胞仪上检测。
人源化抗体4G10H1L1和4G10H3L3与T细胞的结合的结果显示于图9中。如图中所示,4G10H1L1和4G10H3L3抗体可以有效地结合T细胞表面上的CTLA-4靶蛋白,并且它们的结合效率是剂量依赖性的。
实施例8:混合淋巴细胞反应:细胞因子IFN-γ和IL-2的分泌
使用Ficoll-Paque Plus (GE Healthcare, 批号:171440-02)分离PBMC的细胞,并将IL-4 (Peprotech, K2513, 1000U/ml)和GM-CSF (Peprotech, H1513, 1000U/ml)添加至分离的细胞中。在诱导6天之后,添加TNF-α (Peprotech, G1513, 200U/ml)以诱导DC细胞3天。
从PBMC分离T细胞,并以10:1的比率与DC细胞混合。以不同浓度添加所述抗体(或作为对照的hIgG)。在孵育5-6天之后,分别使用IFN-γ(购自Dakewe Co.)和IL-2(购自Dakewe Co.)的ELISA试剂盒测定分泌的IFN-γ和IL-2的量。
在DC细胞和T细胞的混合培养之后测定IFN-γ分泌的结果显示于图10中。在DC细胞和T细胞的混合培养之后测定IL-2分泌的结果显示于图11中。
如图中所示,抗体4G10H1L1和4G10H3L3可以有效地诱导混合淋巴细胞分泌IFN-γ和IL-2,其中抗CTLA4抗体4G10H1L1和4G10H3L3在100 nM的浓度时诱导IFN-γ分泌的效果优于对照抗体10D1的效果(图10)。
尽管已经详细描述了本发明的具体实施方案,但本领域技术人员根据说明书中公开的教导将理解,可以对细节进行各种改变和修改,其中所有都落在本发明的保护范围中。在所附权利要求及其等同方案中阐述了本发明的全部范围。
序列表
<110> Akeso Biopharma, Inc.
Li, Baiyong
Xia, Yu
Wang, Zhongmin
Zhang, Peng
Pang, Xinghua
<120> 抗CTLA4抗体
<130> 24359
<150> PCT/CN2016/096357
<151> 2016-08-23
<160> 36
<170> PatentIn version 3.5
<210> 1
<211> 364
<212> PRT
<213> 人工序列
<220>
<223> CTLA4-mFc融合蛋白
<400> 1
Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala Ser Ser Arg Gly
1 5 10 15
Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly Lys Ala Thr Glu
20 25 30
Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln Val Thr Glu Val
35 40 45
Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr Phe Leu Asp Asp
50 55 60
Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val Asn Leu Thr Ile
65 70 75 80
Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile Cys Lys Val Glu
85 90 95
Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly Asn Gly Thr Gln
100 105 110
Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser Asp Glu Asn Leu
115 120 125
Tyr Phe Gln Gly Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys
130 135 140
Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe
145 150 155 160
Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val
165 170 175
Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile
180 185 190
Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr
195 200 205
His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro
210 215 220
Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val
225 230 235 240
Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro
245 250 255
Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu
260 265 270
Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp
275 280 285
Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr
290 295 300
Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser
305 310 315 320
Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu
325 330 335
Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His
340 345 350
His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
355 360
<210> 2
<211> 1092
<212> DNA
<213> 人工序列
<220>
<223> CTLA4-mFC融合体
<400> 2
gcaatgcatg tcgcacagcc tgcagtggtc ctggcaagct ccaggggaat cgctagcttc 60
gtgtgcgaat acgcttcccc aggcaaggca accgaggtcc gggtgacagt cctgagacag 120
gccgacagcc aggtgacaga agtctgcgcc gctacttata tgatgggcaa cgagctgacc 180
tttctggacg atagcatttg taccgggaca tctagtggaa accaagtgaa tctgaccatc 240
cagggcctgc gcgctatgga cacagggctg tacatttgta aagtggagct gatgtatccc 300
cctccatact atctgggaat cggcaacggg acccagatct acgtgattga tcctgaacca 360
tgccccgact ccgatgagaa tctgtatttc cagggaccac gaggccccac aattaagcca 420
tgtccccctt gcaaatgtcc tgcaccaaac ctgctgggag gaccaagcgt gttcatcttt 480
ccacccaaga tcaaggacgt gctgatgatc tcactgagcc ccattgtgac ctgcgtggtc 540
gtggacgtga gcgaggacga tcctgatgtg cagatcagtt ggttcgtcaa caatgtggaa 600
gtccacacag ctcagactca gacccatagg gaggattaca atagtactct gcgcgtcgtg 660
tcagcactgc ccattcagca ccaggactgg atgagcggca aggagttcaa gtgcaaagtg 720
aacaacaagg atctgcccgc acctatcgag agaactattt ccaagcctaa agggtctgtg 780
agggccccac aggtgtatgt cctgcctcca cccgaggaag agatgactaa gaaacaggtg 840
acactgactt gtatggtcac cgacttcatg cccgaagata tctacgtgga gtggactaac 900
aatgggaaga ccgaactgaa ctataaaaat acagagcctg tgctggactc agatggaagc 960
tactttatgt atagcaagct gcgagtggaa aagaaaaact gggtcgagcg gaacagctac 1020
tcttgtagtg tggtccacga agggctgcat aatcaccaca ccactaaatc attctcccga 1080
actccaggca aa 1092
<210> 3
<211> 372
<212> DNA
<213> 小家鼠
<400> 3
caggtcaagc tgcaggagtc tggacctgag ctggtgaagc ctggagcttc aatgaagata 60
tcctgcaagg cttctggtta ctcattcact ggctacacca tgaactgggt gaagcagagc 120
catggaaaga accttgaatg gattggactt attaatcctt acaataatat tactaactac 180
aaccagaagt tcatgggcaa ggccacattt actgtagaca agtcatccag cacagcctac 240
atggaactcc tcagactgac atctgaagac tctggagtct atttctgtgc aagactcgac 300
tataggtctt attggggcca agggactctg gtcactgtct ctgcagccaa aacgacaccc 360
ccatctgtct at 372
<210> 4
<211> 115
<212> PRT
<213> 小家鼠
<400> 4
Gln Val Lys Leu Gln Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Asn Ile Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Met Gly Lys Ala Thr Phe Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Leu Arg Leu Thr Ser Glu Asp Ser Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 5
<211> 378
<212> DNA
<213> 小家鼠
<400> 5
caggctgttg tgactcagga atctgcactc accacatcac ctggtgaaac agtcacactc 60
acttgtcgct caagtactgg ggctgttaca actagtaact ttgccaactg ggtccaagaa 120
aaaccagatc atttattcac tagtctaata ggtggtacca acaaccgagc tccaggtgtt 180
cctgccagat tctcaggctc cctgattgga gacaaggctg ccctcaccat cacaggggca 240
cagactgagg atgaggcaat atatttctgt gctctatggt acagcaacca ttgggtgttc 300
ggtggaggaa ccaaactgac tgtcctaggc cagcccaagt cttcgccatc agtcaccctg 360
tttcaagggc aattctgc 378
<210> 6
<211> 126
<212> PRT
<213> 小家鼠
<400> 6
Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu
1 5 10 15
Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Phe Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Ser
35 40 45
Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala
65 70 75 80
Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro
100 105 110
Lys Ser Ser Pro Ser Val Thr Leu Phe Gln Gly Gln Phe Cys
115 120 125
<210> 7
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 4G10H1L1的人源化轻链可变区
<400> 7
caggtgcagc tggtggagtc tggggccgag ctggtgaagc ccggcgcctc catgaagatc 60
tcttgcaagg ccagcggata cagtttcact ggctatacca tgaactgggt caaacaggct 120
ccaggacagg gactggagtg gatcgggctg attaatcctt acaacaacat caccaactac 180
aaccagaagt tcatgggaaa agcaaccttt acagtggaca agagcatttc cacagcctac 240
atggaactga gccggctgac ttcagacgat agcggggtct atttttgtgc aaggctggat 300
tatcgctctt actgggggca gggaactctg gtcactgtct ccgct 345
<210> 8
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 4G10H1L1的人源化重链可变区
<400> 8
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Asn Ile Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Met Gly Lys Ala Thr Phe Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Ser Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 9
<211> 327
<212> DNA
<213> 人工序列
<220>
<223> 4G10H1L1的人源化轻链可变区
<400> 9
caggctgtcg tcactcagga accttcactg actgtgagcc caggaggaac tgtcaccctg 60
acatgcggaa gctccaccgg agcagtgacc acatccaact tcgccaattg ggtccaggaa 120
aagccaggcc aggcatttcg atccctgatc ggaggcacaa acaatcgggc ttcttgggtg 180
cccgcaagat tctcaggaag cctgctgggg ggaaaagccg ctctgaccat tagtggcgct 240
cagcctgagg acgaagccga gtacttctgc gctctgtggt atagcaacca ctgggtgttt 300
ggcgggggaa caaagctgac tgtgctg 327
<210> 10
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 4G10H1L1的人源化轻链可变区
<400> 10
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Phe Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Ala Phe Arg Ser
35 40 45
Leu Ile Gly Gly Thr Asn Asn Arg Ala Ser Trp Val Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Phe Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 11
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 4G10H3L3的人源化重链可变区
<400> 11
caggtgcagc tggtcgagtc tggggccgaa gtgaagaaac ccggcgcctc agtgaaggtc 60
agctgcaagg ccagcgggta cagtttcact ggatatacca tgaactgggt ccgacaggcc 120
cctggccagg ggctggagtg gatcggcctg attaaccctt acaacaacat cactaactac 180
gcacagaagt tccaggggag agtgaccttt acagtggaca ccagcatttc cacagcctac 240
atggaactgt cccggctgag atctgacgat acaggcgtgt acttctgcgc taggctggat 300
taccgcagct attggggaca gggcacactg gtgactgtca gcgca 345
<210> 12
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 4G10H3L3的人源化重链可变区
<400> 12
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Asn Ile Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Phe Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 13
<211> 327
<212> DNA
<213> 人工序列
<220>
<223> 4G10H3L3的人源化轻链可变区
<400> 13
caggctgtcg tcactcagga accttcactg accgtgtctc ctggcgggac tgtcaccctg 60
acatgcggca gctccacagg ggccgtgacc acaagtaact tcccaaattg ggtccagcag 120
aagccaggac aggctccccg gagtctgatc ggaggcacca acaacaaggc cagctggaca 180
cccgcacggt tcagcggcag cctgctgggc ggcaaggccg ctctgacaat tagcggagcc 240
cagcctgagg acgaagccga gtactattgc gctctgtggt actccaacca ctgggtgttc 300
ggcggcggca ccaagctgac tgtgctg 327
<210> 14
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 4G10H3L3的人源化轻链可变区
<400> 14
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Phe Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Ser
35 40 45
Leu Ile Gly Gly Thr Asn Asn Lys Ala Ser Trp Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 15
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 4G10H4的人源化重链可变区
<400> 15
caggtgcagc tggtcgagtc tggggccgaa gtgaagaaac ccggcgcctc agtgaaggtc 60
agctgcaagg ccagcgggta cagtttcact ggatatacca tgaactgggt ccgacaggcc 120
cctggccagg ggctggagtg gatcggcctg attaaccctt acaacgacat cactaactac 180
gcacagaagt tccaggggag agtgaccttt acagtggaca ccagcatttc cacagcctac 240
atggaactgt cccggctgag atctgacgat acaggcgtgt acttctgcgc taggctggat 300
taccgcagct attggggaca gggcacactg gtgactgtca gcgca 345
<210> 16
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 4G10H4的人源化重链可变区
<400> 16
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Asp Ile Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Phe Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 17
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 4G10H5的人源化重链可变区
<400> 17
caggtgcagc tggtcgagtc tggggccgaa gtgaagaaac ccggcgcctc agtgaaggtc 60
agctgcaagg ccagcgggta cagtttcact ggatatacca tgaactgggt ccgacaggcc 120
cctggccagg ggctggagtg gatcggcctg attaaccctt acaacaacat cgataactac 180
gcacagaagt tccaggggag agtgaccttt acagtggaca ccagcatttc cacagcctac 240
atggaactgt cccggctgag atctgacgat acaggcgtgt acttctgcgc taggctggat 300
taccgcagct attggggaca gggcacactg gtgactgtca gcgca 345
<210> 18
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 4G10H5的人源化重链可变区
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Asn Ile Asp Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Phe Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 19
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人源化4G10可变重链区共有序列
<220>
<221> X
<222> (11)..(11)
<223> Val或Leu
<220>
<221> X
<222> (18)..(18)
<223> Val或Met
<220>
<221> X
<222> (20)..(20)
<223> Val或Ile
<220>
<221> X
<222> (34)..(34)
<223> Met或Val或Leu或Ile或Gly或Ala或Ser或Thr
<220>
<221> X
<222> (38)..(38)
<223> Arg或Lys
<220>
<221> X
<222> (56)..(56)
<223> Asn或Asp或Glu
<220>
<221> X
<222> (58)..(58)
<223> Thr或Asp或Glu或Gly或Ala
<220>
<221> X
<222> (61)..(61)
<223> Ala或Asn
<220>
<221> X
<222> (65)..(65)
<223> Gln或Met
<220>
<221> X
<222> (67)..(67)
<223> Arg或Lys
<220>
<221> X
<222> (68)..(68)
<223> Val或Ala
<220>
<221> X
<222> (74)..(74)
<223> Thr或Lys
<220>
<221> X
<222> (87)..(87)
<223> Arg或Thr
<220>
<221> X
<222> (91)..(91)
<223> Thr或Ser
<400> 19
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Xaa Lys Lys Pro Gly Ala
1 5 10 15
Ser Xaa Lys Xaa Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Thr Xaa Asn Trp Val Xaa Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Leu Ile Asn Pro Tyr Asn Xaa Ile Xaa Asn Tyr Xaa Gln Lys Phe
50 55 60
Xaa Gly Xaa Xaa Thr Phe Thr Val Asp Xaa Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Xaa Ser Asp Asp Xaa Gly Val Tyr Phe Cys
85 90 95
Ala Arg Leu Asp Tyr Arg Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ala
115
<210> 20
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化4G10可变轻链区共有序列
<220>
<221> X
<222> (35)..(35)
<223> Pro或Ala
<220>
<221> X
<222> (40)..(40)
<223> Gln或Glu
<220>
<221> X
<222> (46)..(46)
<223> Pro或Phe
<220>
<221> X
<222> (56)..(56)
<223> Lys或Arg或除了Met或Cys以外的任何其他氨基酸
<220>
<221> X
<222> (58)..(58)
<223> Ser或Pro
<220>
<221> X
<222> (60)..(60)
<223> Thr或Val
<220>
<221> X
<222> (89)..(89)
<223> Tyr或Phe
<220>
<221> X
<222> (93)..(93)
<223> Trp或除了Met或Cys以外的任何氨基酸
<220>
<221> X
<222> (98)..(98)
<223> Trp或除了Met或Cys以外的任何氨基酸
<400> 20
Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser
20 25 30
Asn Phe Xaa Asn Trp Val Gln Xaa Lys Pro Gly Gln Ala Xaa Arg Ser
35 40 45
Leu Ile Gly Gly Thr Asn Asn Xaa Ala Xaa Trp Xaa Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Ile Ser Gly Ala
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Xaa Cys Ala Leu Xaa Tyr Ser Asn
85 90 95
His Xaa Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 21
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR1共有序列
<220>
<221> X
<222> (4)..(4)
<223> Met或Val或Leu或Ile或Gly或Ala或Ser或Thr
<400> 21
Gly Tyr Thr Xaa Asn
1 5
<210> 22
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR2共有序列
<220>
<221> X
<222> (7)..(7)
<223> Asn或Asp
<220>
<221> X
<222> (9)..(9)
<223> Thr或Asp或Glu或Gly或Ala
<220>
<221> X
<222> (12)..(12)
<223> Ala或Asn
<220>
<221> X
<222> (16)..(16)
<223> Gln或Met
<400> 22
Leu Ile Asn Pro Tyr Asn Xaa Ile Xaa Asn Tyr Xaa Gln Lys Phe Xaa
1 5 10 15
Gly
<210> 23
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR3序列
<400> 23
Leu Asp Tyr Arg Ser Tyr
1 5
<210> 24
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR1共有序列
<220>
<221> X
<222> (13)..(13)
<223> Pro或Ala
<400> 24
Gly Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Phe Xaa Asn
1 5 10
<210> 25
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR2共有序列
<220>
<221> X
<222> (5)..(5)
<223> Lys或Arg或除了Met或Cys以外的任何氨基酸
<220>
<221> X
<222> (7)..(7)
<223> Ser或Pro
<400> 25
Gly Thr Asn Asn Xaa Ala Xaa
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR3共有序列
<220>
<221> X
<222> (3)..(3)
<223> Trp或除了Met或Cys以外的任何氨基酸
<220>
<221> X
<222> (8)..(8)
<223> Trp或除了Met或Cys以外的任何氨基酸
<400> 26
Ala Leu Xaa Tyr Ser Asn His Xaa
1 5
<210> 27
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR1序列
<400> 27
Gly Tyr Ser Phe Thr Gly Tyr Thr
1 5
<210> 28
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR2
<220>
<221> X
<222> (6)..(6)
<223> Asn或Asp或Glu
<220>
<221> X
<222> (8)..(8)
<223> Thr或Asp或Glu或Gly或Ala
<400> 28
Ile Asn Pro Tyr Asn Xaa Ile Xaa
1 5
<210> 29
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 4G10 HCDR3
<400> 29
Ala Arg Leu Asp Tyr Arg Ser Tyr
1 5
<210> 30
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR1
<400> 30
Thr Gly Ala Val Thr Thr Ser Asn Phe
1 5
<210> 31
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR2
<400> 31
Gly Thr Asn
1
<210> 32
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 4G10 LCDR3
<220>
<221> X
<222> (3)..(3)
<223> Trp或除了Met或Cys以外的任何氨基酸
<220>
<221> X
<222> (8)..(8)
<223> Trp或除了Met或Cys以外的任何氨基酸
<400> 32
Ala Leu Xaa Tyr Ser Asn His Xaa Val
1 5
<210> 33
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 示例性重链IgG1恒定结构域
<400> 33
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 34
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 示例性人κ链恒定结构域
<400> 34
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 35
<211> 443
<212> PRT
<213> 人工序列
<220>
<223> 10D1重链
<400> 35
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 36
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 10D1轻链
<400> 36
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
Claims (27)
1.结合人CTLA4的抗体或其抗原结合片段,其包含重链可变区和/或轻链可变区,其中
a) 所述重链可变区包含:
包含SEQ ID NO:21或SEQ ID NO:27的氨基酸序列的HCDR1,
包含SEQ ID NO:22或SEQ ID NO:28的氨基酸序列的HCDR2,和
包含SEQ ID NO:23或SEQ ID NO:29的氨基酸序列的HCDR3;和/或
b) 所述轻链可变区包含:
包含SEQ ID NO:24或SEQ ID NO:30的氨基酸序列的LCDR1,
包含SEQ ID NO:25或SEQ ID NO:31的氨基酸序列的LCDR2,和
包含SEQ ID NO:26或SEQ ID NO:32的氨基酸序列的LCDR3。
2.权利要求1的抗体或抗原结合片段,其选自:
a) 抗体或其抗原结合片段,其包含:重链可变区,其包含:包含SEQ ID NO:21的氨基酸序列的HCDR1,包含SEQ ID NO:22的氨基酸序列的HCDR2,和包含SEQ ID NO:23的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:24的氨基酸序列的LCDR1,包含SEQID NO:25的氨基酸序列的LCDR2,和包含SEQ ID NO:26的氨基酸序列的LCDR3,
b) 抗体或其抗原结合片段,其包含:重链可变区,其包含:包含SEQ ID NO:21(其中X1 =M)的氨基酸序列的HCDR1,包含SEQ ID NO:22 (其中X1 = N或D,X2 = T或D,X3 = A且X4=Q)的氨基酸序列的HCDR2,和包含SEQ ID NO:23的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:24(其中X1 = P)的氨基酸序列的LCDR1,包含SEQ ID NO:25(其中X1 =K且X2 =S)的氨基酸序列的LCDR2,和包含SEQ ID NO:26(其中X1 = W且X2 = W)的氨基酸序列的LCDR3,
c) 抗体或其抗原结合片段,其包含:重链可变区,其包含:包含SEQ ID NO:27的氨基酸序列的HCDR1,包含SEQ ID NO:28的氨基酸序列的HCDR2,和包含SEQ ID NO:29的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:30的氨基酸序列的LCDR1,包含SEQID NO:31的氨基酸序列的LCDR2,和包含SEQ ID NO:32的氨基酸序列的LCDR3,
d) 抗体或其抗原结合片段,其包含:重链可变区,其包含:包含SEQ ID NO:27的氨基酸序列的HCDR1,包含SEQ ID NO:28 (其中X1 = N或D,X2 = T或D)的氨基酸序列的HCDR2,和包含SEQ ID NO:29的氨基酸序列的HCDR3;和/或轻链可变区,其包含:包含SEQ ID NO:30的氨基酸序列的LCDR1,包含SEQ ID NO:31的氨基酸序列的LCDR2,和包含SEQ ID NO:32(其中X1= W且X2 = W)的氨基酸序列的LCDR3。
3.权利要求1或2的抗体或抗原结合片段,其选自:
a) 抗体或其抗原结合片段,其包含SEQ ID NO:4的重链可变区和/或SEQ ID NO:6的轻链可变区;
b) 抗体或其抗原结合片段,其包含SEQ ID NO:8的重链可变区和/或SEQ ID NO:10的轻链可变区;
a) 抗体或其抗原结合片段,其包含SEQ ID NO:12的重链可变区和/或SEQ ID NO:14的轻链可变区;
b) 抗体或其抗原结合片段,其包含SEQ ID NO:16的重链可变区和/或SEQ ID NO:14的轻链可变区;
c) 抗体或其抗原结合片段,其包含SEQ ID NO:18的重链可变区和/或SEQ ID NO:14的轻链可变区;
d) 抗体或其抗原结合片段,其包含SEQ ID NO:19的重链可变区和/或SEQ ID NO:20的轻链可变区;
c) 抗体或其抗原结合片段,其在SEQ ID NO:4的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:6的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代;
d) 抗体或其抗原结合片段,其在SEQ ID NO:8的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:10的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代;
e) 抗体或其抗原结合片段,其在SEQ ID NO:12的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代;
f) 抗体或其抗原结合片段,其在SEQ ID NO:16的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代;
g) 抗体或其抗原结合片段,其在SEQ ID NO:18的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代;
h) 抗体或其抗原结合片段,其在SEQ ID NO:4的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:6的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代,其中所述取代发生在SEQ ID NO:27-32中鉴定的CDR区之外;
i) 抗体或其抗原结合片段,其在SEQ ID NO:8的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:10的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代,其中所述取代发生在SEQ ID NO:27-32中鉴定的CDR区之外;
j) 抗体或其抗原结合片段,其在SEQ ID NO:12的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代,其中所述取代发生在SEQ ID NO:27-32中鉴定的CDR区之外;
k) 抗体或其抗原结合片段,其在SEQ ID NO:16的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代,其中所述取代发生在SEQ ID NO:27-32中鉴定的CDR区之外;
l) 抗体或其抗原结合片段,其在SEQ ID NO:18的可变重链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代和/或在SEQ ID NO:14的可变轻链中包含1、2、3、4、5、6、7、8、9或10个氨基酸取代,其中所述取代发生在SEQ ID NO:27-32中鉴定的CDR区之外;
m) 抗体或其抗原结合片段,其包含与SEQ ID NO:4具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:6具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链;
n) 抗体或其抗原结合片段,其包含与SEQ ID NO:8具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:10具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链;
o) 抗体或其抗原结合片段,其包含与SEQ ID NO:12具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链;
p) 抗体或其抗原结合片段,其包含与SEQ ID NO:16具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链;
q) 抗体或其抗原结合片段,其包含与SEQ ID NO:18具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链;
r) 抗体或其抗原结合片段,其包含与SEQ ID NO:4具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:6具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链,其中任何序列变异发生在SEQ ID NO:27-32中鉴定的CDR区之外;
s) 抗体或其抗原结合片段,其包含与SEQ ID NO:8具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:10具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链,其中任何序列变异发生在SEQ ID NO:27-32中鉴定的CDR区之外;
t) 抗体或其抗原结合片段,其包含与SEQ ID NO:12具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链,其中任何序列变异发生在SEQ ID NO:27-32中鉴定的CDR区之外;
u) 抗体或其抗原结合片段,其包含与SEQ ID NO:16具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链,其中任何序列变异发生在SEQ ID NO:27-32中鉴定的CDR区之外;
v) 抗体或其抗原结合片段,其包含与SEQ ID NO:18具有至少90%、95%、96%、97%、98%或99%同一性的可变重链和/或与SEQ ID NO:14具有至少90%、95%、96%、97%、98%或99%同一性的可变轻链,其中任何序列变异发生在SEQ ID NO:27-32中鉴定的CDR区之外。
4.根据权利要求1-3中任一项所述的抗体或抗原结合片段,其为包含两条重链和两条轻链的人源化抗体。
5.根据权利要求1-4中任一项所述的抗体或抗原结合片段,其为包含人IgG1恒定结构域和人κ恒定结构域的人源化抗体。
6.根据权利要求1-5中任一项所述的抗体或抗原结合片段,其中所述抗原结合片段选自Fab、Fab'、F(ab')2、Fd、Fv、dAb、互补决定区片段、单链抗体(例如,scFv)和双抗体。
7.权利要求1-6中任一项的抗体或抗原结合片段,其为抗体,其中所述抗体在CHO细胞中产生。
8.根据权利要求1-7中任一项所述的抗体或其抗原结合片段,其中所述抗体以小于约1x 10-9 M至约1 x 10-12 M的KD结合人CTLA4,如通过表面等离振子共振(例如,BIACORE)或类似技术(例如KinExa或OCTET)所测定。
9.杂交瘤细胞系LT002,其在2015年6月16日以保藏号CCTCC C201587保藏于中国典型培养物保藏中心(CCTCC)。
10.由权利要求9的杂交瘤细胞系产生的抗体。
11.分离的多肽,其包含选自SEQ ID NO:4、6、8、10、12、14、16、18、19和20的氨基酸序列。
12.药物组合物,其包含根据权利要求1-8和10中任一项所述的抗体或其抗原结合片段,和药学上可接受的载体和/或赋形剂。
13.权利要求12的组合物,其进一步包含选自以下的药剂:
a. 抗PD1抗体或其抗原结合片段;
b. 抗LAG3抗体或其抗原结合片段;
c. 抗VISTA抗体或其抗原结合片段;
d. 抗TIGIT抗体或其抗原结合片段;
e. 抗TIM3抗体或其抗原结合片段;
f. 抗HVEM抗体或其抗原结合片段;
g. 抗CD27抗体或其抗原结合片段;
h. 抗CD137抗体或其抗原结合片段;
i. 抗OX40抗体或其抗原结合片段;
j. 抗CD28抗体或其抗原结合片段;
k. 抗PDL1抗体或其抗原结合片段;
l. 抗PDL2抗体或其抗原结合片段;
m. 抗GITR抗体或其抗原结合片段;
n. 抗ICOS抗体或其抗原结合片段;
o. 抗SIRPα抗体或其抗原结合片段;
p. 抗ILT2抗体或其抗原结合片段;
q. 抗ILT3抗体或其抗原结合片段;
r. 抗ILT4抗体或其抗原结合片段;和
s. 抗ILT5抗体或其抗原结合片段;
t. 抗CD73抗体或其抗原结合片段;和
u. 抗CD47抗体或其抗原结合片段。
14.权利要求13的组合物,其中所述抗PD1抗体或其抗原结合片段选自:派姆单抗或其抗原结合片段和尼沃单抗或其抗原结合片段。
15.缀合物,其包含抗体或其抗原结合片段和缀合的部分,其中所述抗体是根据权利要求1-8和10中任一项所述的抗体或其抗原结合片段,且所述缀合的部分是可检测的标记物。
16.试剂盒,其包含根据权利要求1-8和10中任一项所述的抗体或其抗原结合片段,或根据权利要求15所述的缀合物;并且进一步包含第二抗体,所述第二抗体特异性识别所述抗体或其抗原结合片段;任选地,所述第二抗体进一步包含可检测的标记物,例如放射性同位素、荧光物质、发光物质、生色物质或酶。
17.分离的核酸分子,其编码根据权利要求1-8和10中任一项所述的抗体或抗原结合片段,或权利要求11的多肽。
18.载体,其包含根据权利要求17所述的分离的核酸分子。
19.宿主细胞,其包含根据权利要求17所述的分离的核酸或根据权利要求18所述的载体。
20.产生抗体或抗原结合片段的方法,其包括:
a. 在有利于表达编码权利要求1-8和10的抗体或抗原结合片段中的任一种的重链和/或轻链的多核苷酸的条件下,培养包含所述多核苷酸的宿主细胞;和
b. 任选地,从所述宿主细胞和/或培养基回收所述抗体或抗原结合片段。
21.治疗人个体中的癌症的方法,其包括向所述个体施用有效量的权利要求1-8和10中任一项的抗体或抗原结合片段,其任选地与另外的治疗剂或治疗程序联合。
22.治疗人个体中的感染或感染性疾病的方法,其包括向所述个体施用有效量的权利要求1-8和10中任一项的抗体或抗原结合片段,其任选地与另外的治疗剂或治疗程序联合。
23.用于检测样品中的CTLA4肽或其片段的存在的方法,其包括使所述样品与权利要求1-8和10中任一项的抗体或片段接触,和检测所述抗体或片段和所述肽之间的复合物的存在;其中所述复合物的检测表明CTLA4肽的存在。
24.增加免疫细胞的活性的方法,其包括向有需要的个体施用有效量的权利要求1-8和10中任一项的抗体或抗原结合片段。
25.权利要求24的方法,其中所述方法用于:
a) 治疗癌症;
b) 治疗感染或感染性疾病;或
c) 作为疫苗佐剂。
26.根据权利要求1-8和10中任一项所述的抗体或抗原结合片段,其用于制备药物,所述药物用于:
a. 增加免疫细胞活化;
b. 治疗癌症;或
c. 治疗感染或感染性疾病。
27.权利要求1-8和10的抗体或抗原结合片段用于制备用于治疗癌症的药物的用途,所述药物用于:增加免疫细胞活化;治疗癌症;或治疗感染或感染性疾病。
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US20190177414A1 (en) | 2019-06-13 |
WO2018039097A1 (en) | 2018-03-01 |
EP3503920A1 (en) | 2019-07-03 |
EP3503920A4 (en) | 2020-05-06 |
WO2018035710A1 (en) | 2018-03-01 |
MA46057A (fr) | 2019-07-03 |
US11479608B2 (en) | 2022-10-25 |
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